key: cord-1014405-ux52ouoh
authors: Cui, Dawei; Tang, Yuan; Jiang, Qi; Jiang, Daixi; Zhang, Yun; Lv, Yan; Xu, Dandan; Wu, Jian; Xie, Jue; Wen, Chengping; Lu, Liwei
title: Follicular Helper T Cells in the Immunopathogenesis of SARS-CoV-2 Infection
date: 2021-09-16
journal: Front Immunol
DOI: 10.3389/fimmu.2021.731100
sha: 4b0ebb5cf139e37132e6723f7c16d5f5b62227d0
doc_id: 1014405
cord_uid: ux52ouoh

Coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a serious infectious disease that has led to a global pandemic with high morbidity and mortality. High-affinity neutralizing antibody is important for controlling infection, which is closely regulated by follicular helper T (Tfh) cells. Tfh cells play a central role in promoting germinal center reactions and driving cognate B cell differentiation for antibody secretion. Available studies indicate a close relationship between virus-specific Tfh cell-mediated immunity and SARS-CoV-2 infection progression. Although several lines of evidence have suggested that Tfh cells contribute to the control of SARS-CoV-2 infection by eliciting neutralizing antibody productions, further studies are needed to elucidate Tfh-mediated effector mechanisms in anti-SARS-CoV-2 immunity. Here, we summarize the functional features and roles of virus-specific Tfh cells in the immunopathogenesis of SARS-CoV-2 infection and in COVID-19 vaccines, and highlight the potential of targeting Tfh cells as therapeutic strategy against SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an emerging and acute novel coronavirus mainly transmitted via the respiratory tract, has rapidly caused pandemic-level cases of coronavirus disease 2019 (COVID- 19) , which has a high morbidity and mortality worldwide (1) (2) (3) (4) (5) . Globally, as of 22 June 2021, there have been 178,503,429 confirmed cases of COVID-19, including 3,872,457 deaths from 195 countries and 28 regions according to the World Health Organization (WHO) report (6) . SARS-CoV-2 is a serious threat to human health and life worldwide.

Humans who are immune-naive to SARS-CoV-2 are considered to be a major factor for the COVID-19 pandemic worldwide, and high-affinity neutralizing antibodies are especially essential for the control and clearance of SARS-CoV-2 infection (7) (8) (9) (10) . Several studies have reported sustained antibody responses in patients with SARS-CoV-2 infection, in which specific antibody titers are increased along with the progression of infection (11) (12) (13) (Figure 1) . Notably, the titers of specific antibodies against SARS-CoV-2 are usually low in the first week. When the high cumulative seroconversion rate occurs between 2 and 3 weeks after symptom onset, the titers of neutralizing antibodies are significantly decreased in the early convalescent phase, with the titers of neutralizing antibodies not detectable in some patients, which indicate that several weeks may be needed to generate antibodies against SARS-CoV-2 (12) (13) (14) (15) (16) (17) . These findings suggest that further studies are needed to explore the production and function of neutralizing antibody inSARS-CoV-2 infection.

Antibody responses are closely correlated with CD4 + T cell subsets that play important roles in the control of viral infections, including T helper (Th) 1 (Th1), Th2, and Th17 cells and follicular helper T (Tfh) cells (18, 19) . Among CD4 + Th cell subsets, naive CD4 + T cells differentiated into Tfh cells can promote humoral immunity by mediating the interaction between T cells and B cells, which are essential for the control of viral infections and vaccine responses (19) (20) (21) . Tfh cells, as a novel CD4 + T cell subset, are characterized by the high expression of CXC chemokine receptor 5 (CXCR5), inducible T cell costimulator (ICOS), programmed cell death protein 1 (PD-1), B-cell lymphoma 6 (Bcl-6), and interleukin-21 (IL-21) in both mice and humans and can usually initiate B cells to differentiate into plasma cells that produce high-affinity antibodies to neutralize the virus, such as lymphocytic choriomeningitis virus (LCMV), influenza virus and hepatitis B virus (22) (23) (24) (25) . Loss of Tfh cell function can result in primary immunodeficiencies characterized by impaired humoral immunity, including COVID-19 infection, autosomal-dominant hyper IgE caused by STAT3 deficiency and common variable immunodeficiency (21, 25, 26) . However, the roles and function features of Tfh cells in SARS-CoV-2 infection remain largely unclear (19, 20) . Here, we will discuss the characteristics and functions of Tfh cells in the immunopathogenesis of SARS-CoV-2 infection and in COVID-19 vaccine responses, as well as their implications in eliciting effective immunity against SARS-CoV-2 infection.

Tfh cells can help B cells generate high-affinity antibodies, longlived plasma cells, and memory B cells through functional markers (20, 21) . The markers of Tfh cells are important to identify Tfh cells and their distinct subsets in the lymphoid tissue and circulation, which commonly include chemokine receptor CXCR5, transcription factor Bcl-6, PD-1, CD40 ligand (CD40L), and ICOS in humans and mice (25, (27) (28) (29) . Moreover, the phenotypes of Tfh cells are associated with different stages of immune responses (30, 31) . In secondary lymphoid organs, naïve CD4 + T cells are differentiated into Tfh cells with the upregulation of CXCR5 and downregulation of CC-chemokine receptor 7 (CCR7), which are mediated by antigen-specific conventional dendritic cells (DCs) or monocyte-derived DCs (28, 32, 33) . The increased CXCR5 and decreased CCR7contribute to the migration of Tfh cells toward CXCchemokine ligand 13 (CXCL13)-enriched B lymphoid follicles in the germinal center (GC) (28, 34) . The specific transcription factor Bcl-6 is selectively expressed in Tfh cells but is highly expressed in CXCR5 hi CCR7 low/-Tfh cells in human and mouse GCs (34) (35) (36) (37) . The IL-21 cytokine is highly and specifically secreted by Tfh cells, which promotes the proliferation of Tfh cells and helps B cell differentiation and antibody secretion, which is characteristic of Tfh cells (38) (39) (40) (41) (42) . ICOS deficiency significantly reduces GC reactions and Tfh cells in mice and humans, which indicates that ICOS expressed in Tfh cells is essential for the differentiation and maintenance of Tfh cells, GC formation, B cell differentiation and antibody responses (43) (44) (45) . ICOS, as a key costimulatory molecule, can also induce the secretion of IL-21 in Tfh cells (45) (46) (47) . HighPD-1 expression on Tfh cells can significantly promote the differentiation and activity of Tfh cells (48) (49) (50) . Collectively, Tfh cells are commonly identified as having three phenotypes: canonical GC Tfh cells with PD-1 ++ and ICOS ++ Bcl-6 + CCR7 -CXCR5 ++ CD4 + T cells, precursor-Tfh (Pre-Tfh) cells characterized as PD-1 + ICOS + Bcl-6 low CCR7 low CXCR5 + CD4 + T cells, and memory Tfh cells similar to Pre-Tfh cells in lymphoid tissue (36, (50) (51) (52) . In GC, Tfh cells are responsible for regulating B cell differentiation into memory B cells and plasma cells, controlling the selection of high-affinity antibody production and the development of long-term humoral immunity (53) (54) (55) (56) .

Circulating Tfh (cTfh) cells in the peripheral blood are usually composed of two distinctive phenotypes: effector memory Tfh cells (PD-1 + ICOS + CCR7 low BCL-6 -CXCR5 + CD4 + T cells) and central memory Tfh cells (PD-1 -ICOS -CCR7 high BCL-6 -CXCR5 + CD4 + T cells) (32, 57, 58) . Additionally, based on the expression of CXCR3 and CCR6, cTfh cells are further divided into three subsets: Tfh1 (CXCR3 + CCR6 -), Tfh2 (CXCR3 -CCR6 -), Tfh17 (CXCR3 -CCR6 + ), and Tfh1/17 (CXCR3 + CCR6 + ) cells, which share the signature transcription factors and cytokines of Th1 (T-bet and IFN-g), Th2 (GATA3, IL-4, IL-5 and IL-13), Th17 (RORgt, IL-17 and IL-22) cells, respectively (32, 58, 59) . cTfh2 and cTfh17 cells can induce B cell differentiation and antibody secretion and regulate immunoglobulin (Ig) isotype switching. cTfh1 cells are commonly considered not to be a helper for B cells, but ICOS + PD-1 high CCR7 low cTfh1 cells effectively regulate B cell differentiation and induce antibody responses (59) (60) (61) (62) (63) (64) (65) . These studies display functionally distinct cTfh cell subsets based on ICOS, PD-1, and CCR7 expression, as well as CXCR3 and CCR6. Moreover, these novel subsets are different from Th1, Th2 and Th17 cells but share some of their characteristics. Additionally, Tfh-like cells have also been identified in non-lymphoid tissues, including the synovium of arthritis, skin and salivary glands of patients, which commonly express low or undetectable CXCR5 and Bcl-6 and high PD-1, ICOS, OX40 and IL-21 compared to Tfh cells in secondary lymphoid organs, which also express tissuespecific chemokine receptors, including CCR2, CCR5, CX3Cchemokinereceptor 1 (CX3CR1) and CXCR4 (52, (66) (67) (68) (69) (70) (71) . Recently, Tfh13 cells, a novel Tfh cell subset that secretes IL-4 and IL-13, were shown to be responsible for IgE production in human and mouse allergies and to highly express the transcription factors Bcl-6 and GATA3 (72) (73) (74) . Current studies indicate that distinct phenotypes of Tfh cells are critical for B cell differentiation and high-affinity antibody production ( Table 1) . Interestingly, follicular regulatory T (Tfr) cells are considered a subset of Foxp3 + Treg cells in the GC that are initiated from Foxp3 +/precursors but not from Tfh cells (75) (76) (77) (78) . Tfr cells share canonical Tfh cell molecules, including CXCR5, Bcl-6, PD-1 and ICOS, as well as Treg cell molecules, including CD25, Foxp3, Blimp-1 and CTLA-4 (79) (80) (81) (82) . Importantly, Tfr cells, similar to Treg cells, play a critical role in immunosuppression, rather than Tfh cells, which can limit GC responses and suppress the activation of Tfh cells and B cells within GCs through inhibitory molecules, including CTLA-4, PD-1, IL-10 and TGF-b secretion. The balance of Tfh/Tfr cells is essential to maintain immune homeostasis and mediate humoral immunity (63, 66, (82) (83) (84) (85) .

Tfh cell differentiation is regulated by multiple complex factors and stages. Naïve CD4 + T cells are primed by binding their T cell receptors with peptide-loaded major histocompatibility complex (MHC) class II (pMHC-II) on professional antigen-presenting cells (APCs), such as DCs and monocytes. Strong TCR signaling and continuous antigenic stimulation play critical roles in favoring Tfh cell differentiation by upregulating BATF to promote Bcl-6 expression (86) (87) (88) (89) (90) . The early differentiation of 

Cell subsets Phenotypic markers References Blood Central memory Tfh cells PD-1 -ICOS -CCR7 high Bcl-6 -Blimp-1 -CXCR5 + (32, 57, 58) Effector memory Tfh cells CD40L + /PD-1 + /ICOS + CCR7 low Bcl-6 -Blimp-1 -CXCR5 + cTfh1 cells IFN-g + Bcl-6 -Blimp-1 -CXCR5 + or PD-1 + ICOS + CCR7 low CXCR3 + CCR6 -Bcl-6 -Blimp-1 -CXCR5 + (32, (57) (58) (59) cTfh2 cells IL-4 + Bcl-6 -Blimp-1 -CXCR5 + or CXCR3 -CCR6 -Bcl-6 -Blimp-1 -CXCR5 + cTfh17 cells IL-17A + Bcl-6 -Blimp-1 -CXCR5 + or CXCR3 -CCR6 + Bcl-6 -Blimp-1 -CXCR5 + cTfh1/17 cells IFN-g + IL-17A + Bcl-6 -Blimp-1 -CXCR5 + or CXCR3 + CCR6 + Bcl-6 -Blimp-1 -CXCR5 + cTfh13 cells IL-13 hi IL-4 hi IL-5 hi IL-21 low Bcl-6 + GATA3 + CXCR5 + (72-74)

Pre-Tfh cells PD-1 + ICOS + CCR7 low Bcl-6 low Blimp-1 -CXCR5 + (32, 57, 58) GC Tfh cells PD-1 ++ ICOS ++ CCR7 -Bcl-6 + Blimp-1 -CXCR5 ++ Memory Tfh cells PD-1 + ICOS + CCR7 low Bcl-6 low Blimp-1 -CXCR5 + Tfh cells is sufficiently initiated by DCs predominantly localized to T cell zones of lymphoid organs, which are considered Pre-Tfh cells that upregulate Bcl-6 and CXCR5 and repress CCR7 expression, and Bcl6 + CXCR5 + Pre-Tfh cells are attracted by the chemokine CXCL13 (CXCR5 ligand) produced within the B cell follicle zones toward the T-B border (36, 64, (91) (92) (93) (94) . Pre-Tfh cells migrate to the T-B cell border and interact with cognate B cells to further upregulate Bcl-6, CXCR5, ICOS, PD-1 and IL-21 and downregulate CCR7 expression, which further drives GC-Tfh differentiation and maturation and GC formation. These processes also require available costimulatory molecules and cytokines, including ICOS-ICOSL, OX40-OX40L, PD-1-PD-Ll/ 2, CD40-CD40L, IL-21, IL-6 and IL-12 cytokines (25, 32, 36, (95) (96) (97) (98) (99) (100) (101) (102) .

The transcription factor Bcl-6 in CD4 + T cells is mostly essential for Tfh differentiation and function, and loss of Bcl-6 represses Tfh differentiation, GC formation, B cell differentiation and antibody responses (34, 35, 43) . Bcl6-expressing Tfh cells are also regulated by multiple transcription factors, including positive inductors such as TCF-1 and LEF-1, BATF, NOTCH1/2, and IRF4 and negative regulators such as Blimp-1, FOXO1 and STAT5 (22, 25, 32, (103) (104) (105) (106) (107) (108) (109) (110) . Some costimulatory molecules expressed on Tfh cells are considered markers of Tfh cells, including ICOS, OX40, PD-1 and CD40L, which can also induce Tfh cell differentiation and maintenance (32, 111, 112) . In GC, B cells highly express costimulatory ligands, including ICOSL, CD80, CD86, PD-L1, and PD-L2, which contribute to the maintenance of Tfh cells, and then Tfh cells also mutually promote B cells to differentiate into plasma cells to further produce specific antibodies that mediate humoral immune responses (113, 114) . Bcl-6 induces secretion of the cytokine IL-21, which can promote Tfh cell differentiation by upregulating STAT-1 and STAT-3 signals to further induce Bcl-6 expression, and similarly, the cytokine IL-6 plays a critical role in Tfh cell differentiation by upregulating the STAT1/3-Bcl-6 signal axis (56, 85, 115, 116) . In addition, Tfh1 cells are characterized by IL-21 and IFN-g production, and Tfh1 cell differentiation characterized by increased T-bet and Bcl-6 expression is initiated by phosphorylation of STAT1 and STAT4 in CD4 + T cells that are induced through IL-12, which is partially inhibited by a high concentration of IL-2 that reduces Bcl-6 expression (85, (115) (116) (117) (118) (119) (120) . Tfh2 cells are characterized by IL-4 and IL-21 production; Tfh2 cell differentiation is driven by IL-4 but suppressed by IL-6 via STAT3 signaling, and IL-4-secreted Tfh2 cells contribute to humoral immunity (85, (121) (122) (123) . Tfh17 cells are characterized by IL-21 and IL-17 production; Tfh17 cell differentiation is primed by IL-23, IL-21, ICOS, TGF-b and IL-6, which upregulate Bcl-6 and RORgt expression. Consistent with its well established role in driving B cell response during infection, IL-17 secreted by Tfh17 cells can promote interactions of cognate T-B cells in the GC, inducing the formation of spontaneous GC and Ig isotype class-switching (124) (125) (126) (127) . However, low doses of IL-2, TGF-b and CTLA-4 promote the development of Tfr cells that play critical roles in inhibiting Tfh cell differentiation and GC responses by activating STAT5, Blimp-1, and Bach2 transcription factors in Tfr cells characterized by CXCR5 + Foxp3 + CD4 + T cells (128) (129) (130) (131) (132) (133) . Tfr cells can inhibit Tfh cell and plasma cell differentiation by inhibitory molecules, including CTLA-4, IL-10 and TGF-b; conversely, Tfh cells also inhibit the expansion of Tfr cells by the IL-21 cytokine (27, (131) (132) (133) (134) (135) (136) (137) (138) (139) . This suggests that the balance of Tfh and Tfr cells plays a critical role in regulating B cell differentiation and specific antibody production (140) .

Currently, the SARS-CoV-2 infection pandemic has led to a serious threat to human health worldwide. Neutralizing antibodies of humoral immunity play a critical role in vaccine responses and battles against infectious viruses, including SARS-CoV-2, which is closely associated with Tfh cells differentiation and function (18, 19, 21, (141) (142) (143) (144) (Figure 2) . The role and function of Tfh cells in the control and clearance of SARS-CoV-2 infection and in the development of new vaccines have been investigated.

Previous reports showed that the frequencies of cTfh cells characterized byCXCR5 + ICOS + PD-1 + progressively increased up to 20 days from the onset of infection in a case with non-severe convalescent COVID-19, in addition to elevated specific plasma SARS-CoV-2-binding IgM and IgG antibodies (145) . Single-cell analysis revealed that expanded frequencies of cTfh cells were found in patients with active COVID-19 disease, as well as a high percentage of specific anti-SARS-CoV-2 antibodies, including IgA and IgG (146) . The frequencies of spike (S)-specific cTfh cells (CD3 + CD4 + CD45RA -CXCR5 + ) are consistently elicited after S peptide stimulation in convalescent COVID-19 cases and exhibit a clear phenotypic bias to aCCR6 + CXCR3 -cTfh17 cell phenotype; however, neutralizing activity is inversely correlated with S-specific cTfh17 cell frequencies but positively correlated with S-specific cTfh, cTfh1 (CCR6 -CXCR3 + ) and cTfh2 (CCR6 -CXCR3 -) cell frequencies (147) . Previous reports suggested that expanded CXCR3 + cTfh1 cells positively correlated with the neutralizing antibody response against influenza vaccination and liveattenuated yellow fever vaccination (148, 149) . A recent study showed that increased frequencies of CCR7 low PD-1 + cTfheffectormemory (em), cTfh1 and cTfh2 cells in CXCR5 + CD45RA -CD25 -CD4 + T cells are significantly increased, as well as high IL-1b and TNF-a, and that the frequencies of cTfh1 cells are associated with SARS-CoV-2-specific IgG/IgM antibodies, although CCR7 high PD-1 -cTfh-central memory (cm) and cTfh17 cells in CXCR5 + CD45RA -CD25 -CD4 + T cells are decreased, as well as cTfr cells in Treg cells in convalescent patients compared to healthy subjects. Moreover, the frequencies of high cTfh-em, low cTfh-cm and cTfr cells are positively correlated with disease severity (150) . These observations indicated that cTfh cell phenotypes can induce potent neutralizing responses against SARS-CoV-2 in COVID-19convalescent patients, which will contribute to antibody-based therapeutics and vaccination design for COVID-19.

Additionally, increased frequencies of virus-specific cTfh cells (CD4 + CXCR5 + OX40 + CD40L + ) were observed in acute and convalescent COVID-19 cases, and the frequencies of both SARS-CoV-2-specific cTfh cells and S-specific CCR6 + CXCR3 -cTfh17 cells were closely associated with low disease severity (151) . Longitudinal studies on COVID-19 infection and convalescent subjects indicate that the levels of SARS-CoV-2 antibodies are low and insufficient in humoral immunity response, although the underlying mechanism is poorly understood (11) (12) (13) (14) . The numbers of CD4 + CXCR5 + Tfh, ICOS + Tfh, Bcl-6 + Tfh and Bcl-6 + B cells are decreased in lymph nodes and spleens, which are possibly associated with exclusively abundantTh1 cells, increased Treg cells (but not Tfr cells) and aberrant TNF-a production in COVID-19 lymph nodes in COVID-19 patients, as well as loss of GCs in lymph nodes and spleens from acute and dead COVID-19 patients (26, 152, 153) . These data indicated that defective Tfh cell generation and dysregulated humoral immunity provide a possible mechanistic explanation for the limited durability of antibody responses in COVID-19 disease. Furthermore, low frequencies of CD45RA -PD-1 + CXCR5 + cTfh cells were also observed, but elevated frequencies of activated cTfh (CD38 + ICOS + ) cells were positively correlated with anti-SARS-CoV-2 IgM and IgG titers in hospitalized COVID-19 patients (154) . These findings indicated that activated cTfh cells may be more reflective of recent antigen encounter and emigration from the GCs. Additionally, a singlecell transcriptomic analysis revealed that increased proportions of cytotoxic cTfh cells in hospitalized COVID-19 patients early in the illness are negatively correlated with the IgG levels of anti-spike protein antibodies to SARS-CoV-2, although the total SARSreactive cTfh cells show a positive correlation with anti-spike antibody levels in hospitalized COVID-19 patients but not in nonhospitalized COVID-19 patients, which provided insights into cytotoxic cTfh cells in the distinct disease severities of COVID-19 patients (155) . Moreover, reduced cTfh and PD-1 + cTfh and increased exhausted TIM-3 + cTfh cell frequencies are significantly observed, but the correlations between cTfh cells and anti-SARS-CoV-2IgM and IgG titers were not analyzed in hospitalized COVID-19 patients (156) . These results indicated that cytotoxic cTfh and exhausted cTfh cells may inhibit specific anti-SARS-CoV-2 antibody production, which plays a critical role in severe SARS-CoV-2 infection (157) . In a recent cohort study of COVID-19 patients within six months of recovery, the CXCR5 + CD4 + cTfh cell frequencies were significantly higher in COVID-19 patients in the long-term clinically recovered (20∼26 weeks) cohort (LCR) than in those in the short-time clinically recovered (4∼9 weeks) cohort (SCR). However, the frequencies of cTfh cells in both the LCR and SCR cohorts were lower than those in the healthy donor cohort (HD). Moreover, three cTfh subsets were similar between the LCR and HD cohorts; cTfh1 cell frequencies in the SCR cohort were shown to be significantly low, but cTfh2 and cTfh17 subsets were found to be high compared with the LCR and HD cohorts (158 were observed in asymptomatic or mildly symptomatic patients but not in severely symptomatic patients. These data suggest that asymptomatic and mild patients have weak and transient SARS-CoV-2 antibody responses (159) . During acute COVID-19 infection, expanded activated CD38 + HLA-DR + PD-1 + ICOS + CXCR5 + CD4 + cTfh cells, CD38 + HLA-DR + CXCR3 + cTfh1 cells, and activated CD38 + HLA-DR + Th1 cells emerged, together with cytotoxic CD8 + T cells. The number of activated cTfh1 cells positively correlated with the levels of RBD-and spike-specific antibodies, including IgG, IgA and IgM isotypes (160) . These data indicated that activated cTfh cell responses were associated with robust antibody responses elicited during SARS-CoV-2 infection, which may be valuable as potential biomarkers in vaccine clinical trials. Similarly, CD38 + HLA-DR + cTfh cells, activated CD4 + T cells and cytotoxic CD8 + T cells were expanded in COVID-19 patients, and increased CD38 + HLA-DR + cTfh cells indicated a recent antigen encounter and emigration from the GC of the patients (161) . The frequencies of PD-1 + ICOS + cTfh, cytotoxic CD4 + T and exhausted T cells were strongly expanded in COVID-19 patients, particularly in severe patients compared to healthy individuals, which suggested that extensive T cell dysfunction was associated with COVID-19 severity (162) . In severe COVID-19 patients, the frequencies of CCR6 + cTfh cells and CCR4 + cTfh cells were expanded, but CCR3 + cTfh cells and Th1 cells were low in severe COVID-19 patients compared to healthy individuals (163) . The frequencies of PD-1 + ICOS + cTfh cells, activated cTfh cells and cytotoxic CD8 + T cells were strongly upregulated in COVID-19 patients, particularly in severe patients compared to healthy donors. Moreover, an increase in CD4 + CD127 -CD25 + Treg cells was found in mild patients, and upregulation of CCR4 in activated CD8 + T cells indicated enhanced lung homing in severe COVID-19 patients (164) . Additionally, in rhesus macaques, SARS-CoV-2 infection induces predominantly GC CXCR3 + Tfh cells (but not a PD-1 + + Foxp3 + Tfr cell subset) specific for the SARS-CoV-2 spike and nucleocapsid proteins and produce high titers of antiviral serum IgG and IgM antibodies againstSARS-CoV-2 (165) ( Table 2) . These data indicated that variable Tfh cell subsets dysregulated the humoral immune responses in COVID-19 patients caused by SARS-CoV-2 infection.

The COVID-19 pandemic continues to spread worldwide, and a safe and protective vaccine is urgently needed to effectuate herd protection and control of SARS-CoV-2. Currently, rapid advances have been made in the design and development of SARS-CoV-2 vaccines, such as inactivated vaccines, DNA vaccines, mRNA vaccines and specific SARS-CoV-2 proteins (166) . mRNA-1273 vaccine could significantly induce Th1 and interleukin-21-producing CXCR5 + PD−1 + ICOS + Tfh cell responses, and elicit robust SARS-CoV-2 neutralizing activity, which provided rapid protection in the upper and lower airways from SARS-CoV-2 infection in Rhesus Macaques (167) . When compared to SARS-CoV-2 with recombinant SARS-CoV-2 receptor-binding domain (rRBD) formulated with AddaVax (rRBD-AddaVax) protein vaccine, the SARS-CoV-2 mRNA vaccines encoding RBD and full-length spike protein efficiently induce SARS-CoV-2-specific GC B cell and Tfh cell responses, which promoted specific neutralizing antibody production in vaccinated mice. Interestingly, the rRBD-AddaVax vaccine could elicit high frequencies of IL-4 + Tfh cells (168) . In human vaccination, the BNT162b2 mRNA vaccine for SARS-CoV-2 had significantly elicited AIM + CXCR5 + CD45RA -CD3 + cTfh cell responses, AIM (activation induced marker) cells include CD69 + OX40 + or CD69 + CD40L + orCD69 + 4-1BB + or OX40 + 4-1BB + or CD40L + 4-1BB + or CD40L + OX40 + cells, and the frequency of AIM + cTfh cells is positively correlated with anti-Spike-specific IgA and IgG antibody titers (169) . These findings have indicated that SARS-CoV-2 mRNA vaccines can effectively promote antigen-specific Tfh cell differentiation, B cell responses and the generation of protective antibodies, which are considered as promising candidates for eliciting high-quality adaptive Positively associate with plasma neutralizing activity.

-

cTfh-em and cTfh1 cells expansion.

Positively associate with the SARS-CoV-2-specific antibody titers.

IgM (149) Mild CXCR5 + ICOS + PD-1 + cTfh cells expansion, Correlate with better clinical outcomes. IgM, IgG (144) CD45RA -PD-1 + CXCR5 + cTfh cells reduction, activated cTfh (CD38 + ICOS + ) cells expansion.

Positively correlate with anti-SARS-CoV-2IgM and IgG titers.

Moderate TIM-3 + Tfh-like cells expansion, CD226 + Tfh-like cells reduction. Benefit the maintenance of balanced cellular and humoral immune responses.

-

Severe Tem and Tfh-em cells expansion, Tcm, Tfh-cm, and Tfr cells reduction.

cTfh-em cells negatively correlate with recorded PaO 2 /FiO 2 .

IgG, IgA

Cytotoxic cTfh cells and cytotoxic T helper cells expansion, Treg cells reduction.

Negatively correlate with antibody levels to SARS-CoV-2spike protein.

- Table 3) . Various clinical trials in humans indicate that inactivated SARS-CoV-2 vaccines can induce satisfactory high neutralizing antibody titers that notably reduce the number of patients with severe COVID-19 (173) (174) (175) (176) . These data suggested that SARS-CoV-2 vaccines can safely and effectively promote humoral immune responses, enhance neutralizing antibody titers, and reduce the incidence and mortality of critically ill patients. 

We gratefully appreciate the highly qualified native English speaking editors at American Journal Experts (AJE) for providing reputable English language editing service (Verification code:6107-48C6-A470-D97E-899B) for our manuscript. IgA, IgG (166) full SΔ furin mRNA B220 -CD4 + CD44 hi CD62L -CXCR5 + Bcl-6 + Tfh cells, B220 -CD4 + CD44 hi CXCR5 + PD-1 hi IL-21 + Tfh cells, B220 -CD4 + CD44 hi CXCR5 + Bcl-6 + ICOS + Tfh cells B220 -CD4 + CD44 hi CXCR5 + PD-1 hi IFN-g + Tfh cells notable expansion.

Elicit potent SARS-CoV-2-specific GC B responses, induce robust and specific antibody responses including neutralizing antibody.

IgG1, IgG2a, IgG2b,

RBD mRNA (receptor binding domain, RBD) B220 -CD4 + CD44 hi CD62L -CXCR5 + Bcl-6 + Tfh cells, B220 -CD4 + CD44 hi CXCR5 + PD-1 hi IL-21 + Tfh cells, B220 -CD4 + CD44 hi CXCR5 + Bcl-6 + ICOS + Tfh cells, B220 -CD4 + CD44 hi CXCR5 + PD-1 hi IFN-g + Tfh cells notable expansion Elicit potent SARS-CoV-2-specific GC B responses, induce robust and specific antibody responses including neutralizing antibody.

IgG1, IgG2a, IgG2b, BNT162b2 mRNA vaccine AIM + CXCR5 + CD45RA -CD3 + cTfh cells expansion, AIM cells include CD69 + OX40 + or CD69 + CD40L + orCD69 + 4-1BB + or OX40 + 4-1BB + or CD40L + 4-1BB + or CD40L + OX40 + Positively correlate with anti-spike-specific IgA and IgG titers.

IgA, IgG

Protein vaccines rRBD-AddaVax B220 -CD4 + CD44 hi CD62L -CXCR5 + Bcl-6 + Tfh cells, B220 -CD4 + CD44 hi CXCR5 + PD-1 hi IL-21 + Tfh cells B220 -CD4 + CD44 hi CXCR5 + PD-1 hi IL-4 + Tfh cells slight expansion Delay to elicit potent SARS-CoV-2-specific GC B responses, induce robust and specific antibody responses including neutralizing antibody.

IgG1,

NVX-CoV2373 CXCR5 + PD-1 + CD4 + Tfh cells expansion Induce specific antibody responses including neutralizing antibody.

IgG (169) Spike (S) and receptor binding domain (RBD) protein subunit vaccine CXCR5 ++ BCL-6 + CD4 + CD3 + B220 -Tfh cells expansion Induce specific antibody responses including neutralizing antibody.

IgG (170) StriFK-FH002C PD-1 + CXCR5 + CD4 + Tfh cells expansion Induce specific antibody responses including neutralizing antibody.

IgG, IgG1, IgG2a, IgG2b

Tfh, follicular helper T cell; cTfh, circulating Tfh cell.

Frontiers in Immunology | www.frontiersin.org September 2021 | Volume 12 | Article 731100

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A Familial Cluster of Pneumonia Associated With the 2019 Novel Coronavirus Indicating Person-to-Person Transmission: A Study of a Family Cluster

Clinical Features of Patients Infected With 2019 Novel Coronavirus in Wuhan

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Viral Load Dynamics and Disease Severity in Patients Infected With SARS-CoV-2 in Zhejiang Province, China

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Dynamics and Correlation Among Viral Positivity, Seroconversion, and Disease Severity in COVID-19 : A Retrospective Study

Dynamic Changes in Anti-SARS-CoV-2 Antibodies During SARS-CoV-2 Infection and Recovery From COVID-19

The Janus Face of Follicular T Helper Cells in Chronic Viral Infections

Role of CD4+ T Cells in the Control of Viral Infections: Recent Advances and Open Questions

B Cell Response to Vaccination

CD4(+) T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective

The Transcription Factor TCF-1 Initiates the Differentiation of T(FH) Cells During Acute Viral Infection

Increased Circulating T Follicular Helper Cells Induced via IL-12/21 in Patients With Acute on Chronic Hepatitis B Liver Failure

Hepatitis C Virus-Specific CD4+ T Cell Phenotype and Function in Different Infection Outcomes

Follicular Helper T Cells

Deficiency of Tfh Cells and Germinal Center in Deceased COVID-19 Patients

The Kinase Mtorc1 Promotes the Generation and Suppressive Function of Follicular Regulatory T Cells

Helper Cell Biology: A Decade of Discovery and Diseases

New Insights Into Follicular Helper T Cell Response and Regulation in Autoimmune Pathogenesis

Helper Cells in Space-Time

Helper Cell Heterogeneity: Time, Space, and Function

Helper Cells and T Follicular Regulatory Cells in Rheumatic Diseases

Follicular Helper T Cells in Type 1 Diabetes

Bcl6 and Maf Cooperate to Instruct Human Follicular Helper CD4 T Cell Differentiation

The Transcriptional Repressor Bcl-6 Directs T Follicular Helper Cell Lineage Commitment

Circulating Precursor CCR7(lo)PD-1(Hi) CXCR5(+) CD4(+) T Cells Indicate Tfh Cell Activity and Promote Antibody Responses Upon Antigen Reexposure

Pathophysiology of T Follicular Helper Cells in Humans and Mice

IL-21 Acts Directly on B Cells to Regulate Bcl-6 Expression and Germinal Center Responses

Peripheral TIGIT+ T Follicular Helper Cells That Produce High Levels of Interleukin-21 via OX40 Represent Disease Activity in IgG4-Related Disease

SLAMs Negatively Regulate IL-21 Production in Tfh-Like Cells From Allergic Rhinitis Patients

Unique Expansion of IL-21+ Tfh and Tph Cells Under Control of ICOS Identifies Sjogren's Syndrome With Ectopic Germinal Centres and MALT Lymphoma

Cytokine-Skewed Tfh Cells: Functional Consequences for B Cell Help

Helper Cell Differentiation, Function, and Roles in Disease

The Costimulatory Molecule ICOS Regulates the Expression of C-Maf and IL-21 in the Development of Follicular T Helper Cells and TH-17 Cells

Signaling Mechanisms in T Follicular Helper Cells and Beyond

Dysregulated Generation of Follicular Helper T Cells in the Spleen Triggers Fatal Autoimmune Hepatitis in Mice

Follicular Helper T Cells are Required for Systemic Autoimmunity

PD-1 Controls Follicular T Helper Cell Positioning and Function

PD-1 Immunobiology in Systemic Lupus Erythematosus

TFH Cells in Bystander and Cognate Interactions With B Cells

Sustained Low-Dose Interleukin-2 Therapy Alleviates Pathogenic Humoral Immunity via Elevating the Tfr/Tfh Ratio in Lupus

Follicular Helper T Cells and Follicular Regulatory T Cells in the Immunopathology of Primary Sjogren's Syndrome

The Darker Side of Follicular Helper T Cells: From Autoimmunity to Immunodeficiency

T Follicular Helper Cells in Germinal Center B Cell Selection and Lymphomagenesis

Molecular Control of Follicular Helper T Cell Development and Differentiation

Circulating TFH Cells as a Marker for Early Therapeutic Intervention in T1D

Circulating Follicular Helper-Like T Cells in Systemic Lupus Erythematosus: Association With Disease Activity

T Cell Immune Response Within B-Cell Follicles

Induction of Th1-Biased T Follicular Helper (Tfh) Cells in Lymphoid Tissues During Chronic Simian Immunodeficiency Virus Infection Defines Functionally Distinct Germinal Center Tfh Cells

Tfh1 Cells in Germinal Centers During Chronic HIV/SIV Infection

Phenotype and Functions of Memory Tfh Cells in Human Blood

Roles of Follicular Helper and Regulatory T Cells in Allergic Diseases and Allergen Immunotherapy

Early Th1 Cell Differentiation is Marked by a Tfh Cell-Like Transition

ZIKV Infection Induces Robust Th1-Like Tfh Cell and Long-Term Protective Antibody Responses in Immunocompetent Mice

The Ratio of Blood T Follicular Regulatory Cells to T Follicular Helper Cells Marks Ectopic Lymphoid Structure Formation While Activated Follicular Helper T Cells Indicate Disease Activity in Primary Sjogren's Syndrome

An Enhanced Expression Level of CXCR3 on Tfh-Like Cells From Lupus Skin Lesions Rather Than Lupus Peripheral Blood

Pathologically Expanded Peripheral T Helper Cell Subset Drives B Cells in Rheumatoid Arthritis

Helper-Like Cells in Inflamed Non-Lymphoid Tissues

Shared and Distinct Roles of T Peripheral Helper and T Follicular Helper Cells in Human Diseases

Nasal IL-4(+) CXCR5(+)CD4(+) T Follicular Helper Cell Counts Correlate With Local IgE Production in Eosinophilic Nasal Polyps

Identification of a T Follicular Helper Cell Subset That Drives Anaphylactic IgE

Flow Cytometric Identification of Tfh13 Cells in Mouse and Human

Transcriptional Changes in Peanut-Specific CD4+ T Cells Over the Course of Oral Immunotherapy

Follicular Regulatory T Cells Expressing Foxp3 and Bcl-6 Suppress Germinal Center Reactions

Foxp3+ Follicular Regulatory T Cells Control the Germinal Center Response

Follicular Regulatory T Cells Can be Specific for the Immunizing Antigen and Derive From Naive T Cells

T Follicular Regulatory Cells

T Follicular Regulatory Cells in the Regulation of B Cell Responses

Follicular Regulatory T Cell Biology and its Role in Immune-Mediated Diseases

Follicular Regulatory T Cells Produce Neuritin to Regulate B Cells

Tfr) Cells: Dissecting the Complexity of Tfr-Cell Compartments

Tfh Cells in SARS-CoV-2 Infection

Control of Germinal Center Responses by T-Follicular Regulatory Cells

Unexpected Help: Follicular Regulatory T Cells in the Germinal Center

Are Follicular Regulatory T Cells Involved in Autoimmune Diseases? Front Immunol

Transcriptional and Epigenetic Regulation of Follicular T-Helper Cells and Their Role in Autoimmunity

The Function of Follicular Helper T Cells is Regulated by the Strength of T Cell Antigen Receptor Binding

Batf is Important for IL-4 Expression in T Follicular Helper Cells

Increased Cathepsin S in Prdm1(-/-) Dendritic Cells Alters the TFH Cell Repertoire and Contributes to Lupus

Cutting Edge: Dendritic Cell-Restricted Antigen Presentation Initiates the Follicular Helper T Cell Program But Cannot Complete Ultimate Effector Differentiation

The Role of Dendritic Cells in the Differentiation of T Follicular Helper Cells

Migratory CD11b(+) Conventional Dendritic Cells Induce T Follicular Helper Cell-Dependent Antibody Responses

Priming of T Follicular Helper Cells by Dendritic Cells

A Novel Rabies Vaccine Expressing CXCL13 Enhances Humoral Immunity by Recruiting Both T Follicular Helper and Germinal Center B Cells

Human Lymphoid Organ Cdc2 and Macrophages Play Complementary Roles in T Follicular Helper Responses

ICOS Receptor Instructs T Follicular Helper Cell Versus Effector Cell Differentiation via Induction of the Transcriptional Repressor Bcl6

Early Commitment of Naive Human CD4(+) T Cells to the T Follicular Helper (T(FH)) Cell Lineage is Induced by IL-12

Aberrant Expansion of Circulating CD4(+) CXCR5(+) CCR7(lo) PD1(hi) Tfh Precursor Cells in Idiopathic Inflammatory Myopathy

Role of TRAFs in Signaling Pathways Controlling T Follicular Helper Cell Differentiation and T Cell-Dependent Antibody Responses

T-B-Cell Entanglement and ICOSL-Driven Feed-Forward Regulation of Germinal Centre Reaction

OX40 Ligand Contributes to Human Lupus Pathogenesis by Promoting T Follicular Helper Response

OX40 Cooperates With ICOS To Amplify Follicular Th Cell Development and Germinal Center Reactions During Infection

TCF-1 at the Tfh and Th1 Divergence

LEF-1 and TCF-1 Orchestrate T(FH) Differentiation by Regulating Differentiation Circuits Upstream of the Transcriptional Repressor Bcl6

Notch Signaling Regulates Follicular Helper T Cell Differentiation

Notch Signaling Represents an Important Checkpoint Between Follicular T-Helper and Canonical T-Helper 2 Cell Fate

ICOS Coreceptor Signaling Inactivates the Transcription Factor FOXO1 to Promote Tfh Cell Differentiation

Inhibition of IL-2 Responsiveness by IL-6 is Required for the Generation of GC-TFH Cells

STAT5 is a Potent Negative Regulator of TFH Cell Differentiation

Bcl-6 is the Nexus Transcription Factor of T Follicular Helper Cells via Repressor-of-Repressor Circuits

Transcriptional Regulation of Follicular T-Helper (Tfh) Cells

Molecular Basis of the Differentiation and Function of Virus Specific Follicular Helper CD4(+) T Cells

Human Regulatory B Cells Control the TFH Cell Response

CD4+ Follicular Regulatory T Cells Optimize the Influenza Virus-Specific B Cell Response

Signal Transducer and Activator of Transcription 3 Hyperactivation Associates With Follicular Helper T Cell Differentiation and Disease Activity in Rheumatoid Arthritis

Expansion of T Follicular Helper-T Helper 1 Like Cells Through Epigenetic Regulation by Signal Transducer and Activator of Transcription Factors

Transcription Tipping Points for T Follicular Helper Cell and T-Helper 1 Cell Fate Commitment

The Transcription Factor T-Bet Is Required for Optimal Type I Follicular Helper T Cell Maintenance During Acute Viral Infection

Context-Dependent Role for T-Bet in T Follicular Helper Differentiation and Germinal Center Function Following Viral Infection

Molecular Mechanisms That Control the Expression and Activity of Bcl-6 in TH1 Cells to Regulate Flexibility With a TFH-Like Gene Profile

Insights Into the Role of Follicular Helper T Cells in Autoimmunity

Antigen-Presenting Cell-Derived IL-6 Restricts the Expression of GATA3 and IL-4 by Follicular Helper T Cells

Multi-Source Pathways of T Follicular Helper Cell Differentiation

Interleukin-21 Contributes to Germinal Centre Formation and Immunoglobulin G4 Production in IgG4-Related Dacryoadenitis and Sialoadenitis, So-Called Mikulicz's Disease

Dysregulated Development of IL-17-and IL-21-Expressing Follicular Helper T Cells and Increased Germinal Center Formation in the Absence of RORgammat

RORgammat Licenses the Differentiation and Function of a Unique Subset of Tfh Cells in Response to Immunogenic Self-DNA in Systemic Lupus Erythematosus

Transcriptional Regulation of Adaptive and Innate Lymphoid Lineage Specification

Regulatory T Cells Control Antigen-Specific Expansion of Tfh Cell Number and Humoral Immune Responses via the Coreceptor CTLA-4

Bach2 Attenuates IL-2R Signaling to Control Treg Homeostasis and Tfr Development

Spatial Distribution and Function of T Follicular Regulatory Cells in Human Lymph Nodes

Control of Foreign Ag-Specific Ab Responses by Treg and Tfr

Helper Plasticity Is Orchestrated by STAT3, Bcl6, and Blimp-1 Balancing Pathology and Protection in Malaria. iScience (2020)

The Coinhibitory Receptor CTLA-4 Controls B Cell Responses by Modulating T Follicular Helper, T Follicular Regulatory, and T Regulatory Cells

Conversion of T Follicular Helper Cells to T Follicular Regulatory Cells by Interleukin-2 Through Transcriptional Regulation in Systemic Lupus Erythematosus

SOSTDC1-Producing Follicular Helper T Cells Promote Regulatory Follicular T Cell Differentiation

Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 Transcription Factor

The Multifaceted Functions of Follicular Regulatory T Cells

Follicular Regulatory T Cells: A Novel Target for Immunotherapy?

IL-10-Producing Regulatory B Cells Restrain the T Follicular Helper Cell Response in Primary Sjogren's Syndrome

A Critical Role of IL-17 in Modulating the B-Cell Response During H5N1 Influenza Virus Infection

Human T Follicular Helper (Tfh) Cells and Disease

The Histone Methyltransferase EZH2 Primes the Early Differentiation of Follicular Helper T Cells During Acute Viral Infection

The Metabolic Hormone Leptin Promotes the Function of TFH Cells and Supports Vaccine Responses

Antigen-Dependent Multistep Differentiation of T Follicular Helper Cells and Its Role in SARS-CoV-2 Infection and Vaccination

Breadth of Concomitant Immune Responses Prior to Patient Recovery: A Case Report of non-Severe COVID-19

Next-Generation Sequencing of T and B Cell Receptor Repertoires From COVID-19 Patients Showed Signatures Associated With Severity of Disease

Humoral and Circulating Follicular Helper T Cell Responses in Recovered Patients With COVID-19

Induction of ICOS+CXCR3+CXCR5+ TH Cells Correlates With Antibody Responses to Influenza Vaccination

Dynamic Changes in Circulating T Follicular Helper Cell Composition Predict Neutralising Antibody Responses After Yellow Fever Vaccination

Peripheral CD4+ T Cell Subsets and Antibody Response in COVID-19 Convalescent Individuals

Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations With Age and Disease Severity

Loss of Bcl-6-Expressing T Follicular Helper Cells and Germinal Centers in COVID-19

SARS-CoV-2-Specific T Cells Exhibit Phenotypic Features of Helper Function, Lack of Terminal Differentiation, and High Proliferation Potential

Deep Immune Profiling of COVID-19 Patients Reveals Distinct Immunotypes With Therapeutic Implications

Imbalance of Regulatory and Cytotoxic SARS-CoV-2-Reactive CD4(+) T Cells in COVID-19

Dynamics of NK, CD8 and Tfh Cell Mediated the Production of Cytokines and Antiviral Antibodies in Chinese Patients With Moderate COVID-19

The Single-Cell Landscape of Immunological Responses of CD4+ T Cells in HIV Versus Severe Acute Cui et al. Tfh Cells in SARS-CoV-2 Infection Respiratory Syndrome Coronavirus 2

Alterations in Phenotypes and Responses of T Cells Within 6 Months of Recovery From COVID-19: A Cohort Study

The Dichotomous and Incomplete Adaptive Immunity in COVID-19 Patients With Different Disease Severity

Integrated Immune Dynamics Define Correlates of COVID-19 Severity and Antibody Responses

Highly Armed Cytotoxic Cells and a Shift in Monocytes CD300 Receptors Expression Is Characteristic of Patients With Severe COVID-19

Profound Dysregulation of T Cell Homeostasisand Function in Patients With Severe COVID-19

Characterization of T Lymphocytes in Severe COVID-19 Patients

Upregulation of CCR4 in Activated CD8(+) T Cells Indicates Enhanced Lung Homing in Patients With Severe Acute SARS-CoV-2 Infection

SARS-CoV-2 Induces Robust Germinal Center CD4 T Follicular Helper Cell Responses in Rhesus Macaques

Immunological Mechanisms of Vaccine-Induced Protection Against COVID-19 in Humans

Evaluation of the mRNA-1273 Vaccine Against SARS-CoV-2 in Nonhuman Primates

SARS-CoV-2 mRNA Vaccines Foster Potent Antigen-Specific Germinal Center Responses Associated With Neutralizing Antibody Generation

A Single Dose of the SARS-CoV-2 Vaccine BNT162b2 Elicits Fc-Mediated Antibody Effector Functions and T Cell Responses

SARS-CoV-2 Spike Glycoprotein Vaccine Candidate NVX-CoV2373 Immunogenicity in Baboons and Protection in Mice

Immunogenicity of Prime-Boost Protein Subunit Vaccine Strategies Against SARS-CoV-2 in Mice and Macaques

A Recombinant Spike Protein Subunit Vaccine Confers Protective Immunity Against SARS-CoV-2 Infection and Transmission in Hamsters

Safety and Immunogenicity of an Inactivated SARS-CoV-2 Vaccine, BBIBP-CorV: A Randomised, Double-Blind, Placebo-Controlled, Phase 1/2 Trial

Tolerability, and Immunogenicity of an Inactivated SARS-CoV-2 Vaccine in Healthy Adults Aged 18-59 Years: A Randomised, Double-Blind, Placebo-Controlled, Phase 1/2 Clinical Trial

Tolerability, and Immunogenicity of an Inactivated SARS-CoV-2 Vaccine (CoronaVac) in Healthy Adults Aged 60 Years and Older: A Randomised, Double-Blind, Placebo-Controlled, Phase 1/2 Clinical Trial

Safety and Immunogenicity of an Inactivated SARS-CoV-2 Vaccine, BBV152: Interim Results From a Double-Blind, Randomised, Multicentre, Phase 2 Trial, and 3-Month Follow-Up of a Double-Blind, Randomised Phase 1 Trial

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.