key: cord-0007883-kseaklxn
authors: Mathew, Anuja
title: Regulation and Function of NK and T Cells During Dengue Virus Infection and Vaccination
date: 2018-05-30
journal: Dengue and Zika: Control and Antiviral Treatment Strategies
DOI: 10.1007/978-981-10-8727-1_18
sha: b433da2f7daf45d7ac212d3f9b4364cdfde4eaf9
doc_id: 7883
cord_uid: kseaklxn

The focus of this review is to discuss findings in the last 10 years that have advanced our understanding of human NK cell responses to dengue virus. We will review recently identified interactions of activating and inhibitory receptors on NK cells with dengue virus, human NK responses to natural dengue infection and highlight possible interactions by which NK cells may shape adaptive immune responses. T cell responses to natural dengue infection will be reviewed by Laura Rivino in Chap. 10.1007/978-981-10-8727-1_17. With the advent of numerous dengue vaccine clinical trials, we will also review T and NK cell immune responses to dengue virus vaccination. As our understanding of the diverse functions of NK cell has advanced, it has become increasingly clear that human NK cell responses to viral infections are more complicated than initially recognized.

NK cells are large granular lymphocytes that are a component of the innate immune system. NK cells kill target cells spontaneously without the requirement of priming or the expression of major histocompatibility antigens (MHC) on the target cell. NK cells lack the receptor diversity generated by DNA rearrangement found in prototype members of the adaptive immune response, T and B cells. However, similar to T cells, NK cells are able to distinguish healthy cells from virally infected cells. NK cells produce abundant antiviral cytokines, release cytotoxic granules such as granzyme B and trigger the FAS/TRAIL pathway to induce apoptosis of infected cells [35] . In order to mount a response, NK cells have to integrate signals received from many inhibitory and activating receptors to sense the environment and respond. Regulation of NK cell activity is achieved by a balance between these inhibitory and activating signals although signals received by inhibitory receptors tend to be dominant [21] . Many of the initial insights on NK cell function came from studying chronic viral infections in mice such as LCMV and MCMV [7] . The clearest demonstration that NK cells are important to humans stem from the findings that patients with NK cell deficiencies develop severe, recurrent viral infections [6, 54] . Our knowledge of select receptors on human NK cells modulated by viral A. Mathew (*) Department of Cell and Molecular Biology, Institute for Immunology and Informatics, Providence, RI, USA e-mail: mathewa@uri.edu infection and viral peptides that can modulate NK cell function has significantly advanced in the last decade in the context of human viral infections such as HMCV, HIV and HCV [7, 19] . Some of the findings seen in these human chronic viral infections are beginning to be observed for viral infections such as Influenza and Dengue thus opening up new areas of research that will enhance our understanding of how these innate effector cells can control acute viral infections [1, 4, 57, 58, 72] 

Human NK cells were shown to lyse dengue virus (DENV)-infected cells to a greater degree compared to uninfected cells over 30 years ago [38] . Antibodies to DENV further augmented the lysis of DENV-infected cells by NK cells. The traditional phenotype used to define human NK cells is based on the absence of CD3 (to exclude T cells) and relative expression of CD56 (neural cell adhesion molecule) and CD16 (low-affinity receptor for the Fc portion of immunoglobulin G). It is now appreciated that CD56 "bright" cells can produce cytokines abundantly but are poorly cytolytic while CD56 "dim" cells (which represent 90% of circulating NK cells) produce moderate cytokines when stimulated but are strongly cytolytic [60] . Using [31] . At the time, many of the activating and inhibitory receptors present on NK cells were not identified and the technologies to assess markers on individual NK cells using multiparametric flow cytometry and CyTOF were not available. In a study published in 2008, frequencies of CD56+ CD69+ NK cells were found to be more activated in hospitalized Vietnamese infants with more severe dengue disease [15] . Recently Petitdemange et al. evaluated NK cell activation in patients from Gabon undergoing acute dengue infection [59] . They examined frequencies of subsets of NK cells and included a number of NK cell receptors NKp30, NKG2A, NKp44 and CD161 which was a significant advance from the early studies where only CD56 expression was used to identify NK cells. Compared to healthy donors, NK cells from patients who had DENV-2 infections expressed significantly less NKp30, NKG2A, and CD161, whereas expression of ILT-2 was increased at the early acute and convalescent time point. Interestingly, frequencies of NKp44+ NK cells were elevated at the early acute time point. Principal component analysis highlighted an association between NKp44 and DENV-2 infections. NKp44 has previously been shown to directly interact with the envelope protein of DENV and WNV and this subset of NK cells and its ligand in target cells is worthy of study in other cohorts [30] . While there have been only a few studies that have looked at NK cell responses in clinical cohorts, the data indicate that subsets of NK cells are involved in the immune responses to natural dengue infection thus warranting further study. NK cell responses in individuals receiving live attenuated tetravalent dengue vaccines have not been examined in any detail. Whether different subsets of NK cells respond to vaccination with live attenuated dengue vaccines versus subunit vaccines and inactivated vaccine antigens are currently unknown. Furthermore, whether the magnitude of NK cell responses is different between vaccination and natural infection has not been explored. In a large genome-wide association study (GWAS) performed in 2011, a single nucleotide polymorphism in MICB (ligand for NKG2D) was found to be a susceptibility locus for severe dengue disease dengue shock syndrome in over 2000 Vietnamese children [37] . In a subsequent study by the same group, MICB was also associated with the less severe form of dengue DF in both children and adults in Vietnam [77] . This genetic susceptibility of a SNP in MICB was confirmed in another study in the Thai population. In Cuban individuals (Guzman), a strong association of DF and DHF with MICA 008 and MICB 008 compared to asymptomatic individu- To date, only NKp44 has been shown to directly interact with the E protein of DENV. NK cells can interact with DENV infected APCs by responding to cytokines, interacting with yet to be identified ligands on virus-infected cells and upregulating inhibitory or activating receptors on its surface. This may lead to degranulation and abundant cytokine secretion by NK cells and lysis of virus-infected cells. Alternatively, dominant interaction of inhibitory receptors on NK cells with viral proteins and peptides could dampen responses and represent an immune evasion strategy by DENV. NK cells can also be directed to DENV infected APCs through engagement of CD16 with the Fc receptor of DENV-specific Abs and target cells are lysed through ADCC als [24] . Interestingly soluble MICB levels were increased in the sera between pre-infection and acute illness among infants with symptomatic primary DENV infections in the Philippines and suggest an immune evasion strategy in dengue viral infection [43] . The data suggest that ligands for the activating receptor NKG2D, MICB may be involved in the immune response against DENV.

A direct interaction has been shown between the NK-activating receptor NKp44 and the DENV and WNV envelope protein [30] .

Recombinant NKp44 directly bound purified DENV and WNV envelope proteins. The results suggest that NKp44 expressing NK cells are able to interact directly with the E protein on flavivirusinfected cells.

NK cells express the FcγRIIIA receptor (CD16) that binds the constant (Fc) domain of IgG antibodies. CD16 engagement is a strong activator of NK cell function and allows antigenspecific recruitment of NK responses. Very early on, NK cell-mediated lysis of DENV-2-infected Raji cells was significantly higher when these cells were pre-incubated with DENV immune serum through antibody dependent cell-mediated cytotoxicity (ADCC) [38] . More recently efforts have been made to understand in a prospective cohort whether ADCC activity in sera obtained pre-illness in a prospective cohort correlated with subsequent dengue disease severity and viremia levels. A higher level of ADCC activity measured in immune sera before secondary DENV-3 but not secondary DENV-2 infection was associated with lower subsequent viremia levels [41] . These results suggest a protective role for ADCC antibodies in sera obtained from in some children with secondary infection. In vivo, characteristics of both the Abs and NK cells in each individual are likely to impact the function of these Abs. Future studies should compare the contribution of functionally distinct Abs (those that mediate neutralization versus Abs that mediate ADCC) in the sera of individuals who subsequently develop clinical versus subclinical disease.

In order to understand soluble and membrane found factors important for activating NK cells, Lim et al. used DENV-infected monocyte-derived dendritic cells in co-culture with autologous NK cells from healthy donors [44] . The results suggest that a combination of cytokines type I IFNs, TNF-☐ secreted by DCs and cell surface receptor-ligand interactions all play some part triggering the anti-dengue response of primary human NK cells while each of these in isolation has a low to minimal response on the activation of human NK cells.

A major set of inhibitory receptors important for NK cell licensing is the killer cell immunoglobulin-like receptors (KIRs). The KIR receptors are expressed stochastically, leading to the generation of subpopulations of NK cells within each individual [50] . While only some KIR ligands are known, all are thought to be class I MHC molecules ( [5, 34, 32, 39, 53, 63, 68] .

In contrast to the T-cell receptor, which recognizes a given viral peptide-MHC complex, KIRs typically recognize subsets of MHC class I molecules with common amino acid motifs in their α1 domains ( [13, 33] ). However, several studies have shown that inhibitory KIRs are also sensitive to the specific peptides bound by the HLA molecules [12] . In particular, residues 7 and 8 of endogenously derived peptides bound to MHC class I can promote or abrogate binding of KIR. During viral infection, the peptide repertoire changes and a number of viral peptides are presented on MHC molecules for recognition by cytotoxic T lymphocytes. Changes in the endogenous repertoire of peptides can perturb or continue to maintain inhibition of NK cells (Fig. 18. 2) depending on how strongly the viral peptide is able to bind and replace the endogenous peptide. Several viral peptides (HIV, HCV, SIV) have been shown to modulate KIR-MHC interactions thus providing a mechanism for the virus to modulate the interaction of the inhibitory KIR with its MHC ligand thus preventing the activation of subsets of NK cells [22, 47] . How changes in the peptide repertoire following viral infection alter NK cell recognition in vivo will depend on the relative amounts of viral peptides being presented, the nature of the peptides produced by infection and the frequency of NK cells expressing the relevant KIR. (Fig. 18.1a) , the interaction of an HLA B57 presenting endogenous peptides on an antigen presenting cell (APC) with KIR3DL1 maintains an inhibitory signal in NK cells thus preventing lysis of healthy target APCs. During many viral infections, HLA molecules are downregulated which allows NK cells to get activated and lyse virus-infected APCs (Fig. 18.1b) .

However it is well known that in DENV infection HLA class I molecules are upregulated [79] . We hypothesize that presentation of the NS1 peptide on HLA B57 during the viremic phase in infected individuals maintains the inhibitory interaction with KIR3DL1 (since the tetramer has been shown to bind KIR3DL1) thus delaying the activation of this important subset of NK cells ( Fig. 18.1c, d) . As viremia decreases, Class I expression decreases and NK cells are able to sense the change in Class I expression, triggering their activation during the critical phase of illness (around fever day 0) (Fig. 18.1d ). Our clinical data support our hypothesis but we are yet to show functional alteration of NK cell responses by the NS1 peptide. We are currently using NK cell sensitive TAPimpaired and TAP-blocked target cells (721.221) transfected with HLA alleles in functional assays. Since self-peptide is able to maintain inhibition, the use of TAP blocked and TAP impaired cell lines HLA transfected cell lines are essential to evaluate whether viral peptides added exogenously such as the DENV NS1 peptide can modulate the function of KIR3DL1+ NK cells. We anticipate that additional KIR/HLA interactions occur which are likely to be modulated by viral peptides during acute dengue. [3, 57] . Differences in population origin and the infecting DENV serotype may explain these disparate results. Petitdemange et al. in a subsequent paper assessed NK cell activation by multiparametric flow cytometry in patients with DENV-2, CHIKV or in a few subjects with coinfections [59] . They found different signatures of NK cell responses between the two infections. NK cells in CHIKV infection were activated early and expressed a terminal differentiation pattern with prolonged persistence of NKG2C + CD57+ cells which the authors speculate may contribute to the chronic arthralgia seen in CHIKV infection. DENV-2 infections were associated with an increase in KIR2DL1+ NK cells which recognize HLA-C2. Together, these studies suggest that KIR-MHC interactions are likely to be important during acute dengue infection.

LILRB is an inhibitory receptor present on monocytes, dendritic cells, and NK cells. It interacts with a wide range of MHC Class I molecules and maintains a negative feedback loop to prevent autoimmunity [70] . THE UL-18 protein of HCMV has been shown to bind with higher affinity to LILRB and protect against NK cell recognition in the context of HCMV infection. Recently using dengue-specific antibodies at neutralizing and sub-neutralizing concentrations, mechanisms of antibody-dependent enhancement (ADE) were further characterized in a resistant (THP-1R) and susceptible (THP-1S) subclone of THP-1 cells [14] . In this context, DENV was shown to interact with the inhibitory receptor LILRB. This inhibitory interaction blocked FcγRII signaling and dampened the expression of IFN stimulated genes and enhances DENV replication.

HLA-E is a non-classical MHC molecule that interacts with both activating (CD94C, D, and E) and inhibitory receptors (CD94A). Interaction of HLA-E with the inhibitory receptor NKG2A is of higher affinity compared to the interaction with most known HLA-E/peptide complexes than those transmitting activating signals. A related flavivirus, Japanese Encephalitis virus has been shown to upregulate HLA-E but no work has been published yet for DENV [69] .

NK cells have also been implicated in shaping the adaptive response to viral infections in a number of ways including promoting maturation or elimination of DCs, perforin-dependent elimination of CD8 + T cells, and cytokine production [64] . Waggoner et al. used the model of lymphocytic choriomeningitis virus (LCMV), to show that NK cells can regulate CD4 T-cell-mediated support for the antiviral CD8 T cells [74, 76] . NK cells have also been shown to be important for long-term CD4+ T cell memory and subsequent antibody responses [18] . The data suggest that NK cells continue to participate in immune modulation well after initial infection when NK cells are traditionally thought to be active. In a previous study of CD8+ T cells by Townsley et al. frequencies of the HLA-B57-restricted epitope, were assessed over the course of acute DENV infection [71] . Given the highly conserved nature of this epitope, we predicted that PBMC from donors with secondary dengue infection would have significantly higher frequencies of B57-NS1 26-34 CD8+ T cells compared to PBMC from donors with primary dengue infection. While we detected tetramer-positive T cells in all subjects tested, the frequencies in subjects with secondary infections were not higher than in subjects with primary infections, with one exception.

We speculated that an unidentified factor may dampen activation of CD8+ T cells directed at this epitope but had not yet identified that the NS1 peptide presented on HLA-B57 could bind KIR3DL1 an inhibitory receptor on NK cells.

Our new findings suggest that NK cells could shape CD8+ T cell responses but given the lack of an authentic animal model that mimics human dengue infection it will be challenging to provide definite proof that inhibitory NK cells can modulate adaptive responses at the epitope level in vivo. The varying combinations of inhibitory and activating receptors on NK cells and the number of unknown ligands make it difficult to assess changes in absolute frequencies of subsets of NK cells between subjects with mild or severe dengue illness. Furthermore, for meaningful comparisons to be made samples must be collected at multiple points and compared in subjects with mild and severe dengue disease rather than compare responses in all subjects with dengue disease and responses in healthy subjects. Since the hallmark of dengue hemorrhagic fever DHF (severe disease) is plasma leakage, if NK cells are hypothesized to contribute to DHF, then changes in the frequency or function of subsets of NK cells during or prior to defervescence the critical phase of illness must be demonstrated. In vitro assays will need to be performed in order to understand which receptors and ligands interact with virus-infected cells and are important for cytokine production and cytolytic activity in subsets of NK cells following DENV infection as little information exists to date. Basic biological studies of NK cells and multiple studies using clinical samples in chronic viral infections suggest that subsets of NK cells are an important contributor to the overall immune response. We have a partial understanding of how NK cells can regulate dengue immune responses but these findings point to multiple avenues whereby NK cells may control DENV infection and shape adaptive immune responses.

T cell immune responses to natural dengue infection will be reviewed by Rivino et al. in Chap. 15 .

With the advent of a number of dengue tetravalent vaccine trials, T cell responses are being evaluated in vaccinated individuals [66] . These studies indicate that CD4 and CD8 T cells are directed against a number of epitopes across the entire DENV genome. In support of smaller studies performed in individuals receiving monovalent DENV vaccines, the data indicate that non-structural proteins are dominant targets of T cell responses following tetravalent vaccination as well [51] . There are significant differences in the composition of dengue antigens included in each vaccine which are likely to impact the immune response elicited [66] . Prior flavivirus immunity in many volunteers who received dengue vaccines in endemic countries will also influence the magnitude and quality of T cell immune responses. Here, published work to characterize CD4+ and CD8+ T-cell responses to dengue virus antigens and peptides will be reviewed. The Sanofi Pasteur vaccine is a chimeric Yellow fever virus that expresses the structural components (prM and E) of each of the four serotypes of dengue [65, 66] . In three independent phase 1 clinical trials conducted in Australia and in the USA, Dengue 1-4 and Yellow Fever 17D (YF 17D)-specific CD4 and CD8 cellular responses induced by tetravalent chimeric dengue vaccines (CYD) were analyzed in flavivirusnaive or immune individuals [27] . Significant YF 17D NS3-specific CD8 responses and dengue serotype-specific T helper responses were detected. These responses were dominated by serotype 4 in naive individuals, but a booster vaccination broadened serotype-specific responses. A similar, broader response was seen after primary tetravalent immunization in subjects with pre-existing dengue 1 or 2 immunity caused by prior monovalent live-attenuated dengue vaccination. There was an absence of a Th2 response, and a more dominant response to IFN-☐ compared to TNF-α, for both CD4 and CD8 responses.

CD4 and CD8 T cell responses were assessed before and 28 days after a first and third injection of Sanofi Pasteur live attenuated CYD-TDV and 1 year after the third injection in 80 adolescents and adults enrolled in a phase II trial in Singapore [29] . CD4/IFN-γ and TNF-α responses specific to dengue NS3 were detected before vaccination. Vaccination induced YF-17D-NS3-specific CD8 IFN-γ responses. Using a multiplex analysis of peripheral blood mononuclear cells (PBMC) supernatants after restimulation with each the CYD vaccine viruses, higher levels of IFN-γ were detected compared with TNF-α, and lowlevel IL-13 levels.

The Takeda vaccine is a live-attenuated tetravalent dengue vaccine (TDV) candidate that consists of an attenuated DENV-2 strain (TDV-2), and 3 chimeric viruses containing the premembrane (prM) and envelope (E) genes of DENV-1, -3, and -4 expressed in the context of the TDV-2 genome (TDV-1, TDV-3, TDV-4, respectively). CD8+ T-cell responses in flavivirus-naive human volunteers vaccinated with 2 doses of the Takeda vaccine 90 days apart via two routes (subcutaneous or intradermal) were assessed using overlapping peptide pools against the NSl, NS3 and NS5 proteins [16] . The TDV vaccine-elicited CD8+ T cell TNF-☐ and IFN-☐ responses against the nonstructural NS l, NS3, and NS5 proteins of DENV-2. Responses were highest on day 90 after the first dose and were still detectable on 180 days after the second dose. In addition, CD8+ T cells were multifunctional, producing 2 cytokines simultaneously, and cross-reactive to NS proteins of the other 3 DENV serotypes.

For the NIH vaccine, attenuation was achieved by deleting a portion of the 3 1 untranslated region (UTR) of the dengue genome. Longitudinal specimens were collected in flavivirus-naive volunteers and tested for T cell responses against inactivated DENV antigen preparations made in Vero cells following low dose vaccination with a live attenuated DENV-1 candidate vaccine (DEN1L130) from the NIH. CD4+ T cells were found to secrete IFN-γ, TNF-α and IL-2, 3 weeks following exposure to DENV-1 and were detected upto 6 weeks. T cells produced 2 cytokines simultaneously [45] . There was little crossreactivity in T cell responses.

Weiskopf et al analyzed CD8+ T cell responses in PBMC from healthy naïve volunteers in Vermont who received either monovalent or tetravalent live attenuated DENV vaccine from the NIH [75] . Using peptide pools (9-and 10-mer peptides that were predicted for their binding affinity to 27 major histocompatibility complex (MHC) class I molecules to monovalent and tetravalent DENV vaccines from the NIH. They found broad responses (IFN-☐ and TNF-☐ responses) to both structural and non-structural proteins were elicited in response to a monovalent vaccine (up to 47 months post-vaccination) while responses to a tetravalent vaccine (up to 12 months post-vaccination) were directed against the non-structural proteins.

Immune responses in vaccinated individuals are continuing to be monitored. How durable T cell responses to any of the attenuated vaccines in clinical trials is of interest as waning immunity to dengue is proposed to increase the risk of severe illness. That is what we hope. Our expectation is that during the viremic phase this peptide is able to inibit NK cells. When the viremia ends, there is no longer presentation of the NS1 peptide, and that leads to NKcell inhibition being released. So now suddenly the NK cells get activated and release the cytokines which may contribute to the cytokine storm seen during end of viremia and the critical phase of illness. That is our thinking, but that is still to proven.

Killer-cell immunoglobulin-like receptors (KIR) in severe a (H1N1) 2009 influenza infections

Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA

Influence of KIR genes and their HLA ligands in susceptibility to dengue in a population from southern Brazil

NK cells during dengue disease and their recognition of dengue virusinfected cells

The role of KIR2DS1 in multiple sclerosis: KIR in Portuguese MS patients

Severe herpesvirus infections in an adolescent without natural killer cells

Natural killer cell diversity in viral infection: why and how much?

HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C

2B4, the natural killer and T cell immunoglobulin superfamily surface protein, is a ligand for CD48

The Lilr family: modulators of innate and adaptive immune pathways in health and disease

NKP44, a triggering receptor involved in tumor cell lysis by activated human natural killer cells, is a novel member of the immunoglobulin superfamily

Effects of peptide on NK cell-mediated Mhc I recognition

Peptide selectivity discriminates NK cells from KIR2DL2-and KIR2DL3-positive individuals

Leukocyte immunoglobulin-like receptor B1 is critical for antibody-dependent dengue

Dengue in vietnamese infants--results of infectionenhancement assays correlate with age-related disease epidemiology, and cellular immune responses correlate with disease severity

CD8+ T-cell responses in Flavivirus-Naive individuals following immunization with a live-attenuated tetravalent dengue vaccine candidate

HLA-C is the inhibitory ligand that determines dominant resistance to Lysis by NK1-and NK2-specific natural killer cells

NK cells and their ability to modulate T cells during virus infections

NK cells: tuned by peptide?

Human CD38 and CD16 are functionally dependent and physically associated in natural killer cells

Human NK cell response to pathogens

Hla-CW*0102-restricted HIV-1 P24 epitope variants can modulate the binding of the inhibitory KIR2DL2 receptor and primary NK cell function

KIR2DL4 (CD158D), an NK cell-activating receptor with inhibitory potential

Association of MICA and MICB alleles with symptomatic dengue infection

KIR2DS4 is a product of gene conversion with KIR3DL2 that introduced specificity for HLA-A*11 while diminishing avidity for HLA-C

Early CDd69 expression on peripheral blood lymphocytes from children with dengue hemorrhagic fever

Cellmediated immunity induced by chimeric tetravalent dengue vaccine in naive or flavivirus-primed subjects

Recognition of HLA-A3 and HLA-A11 by KIR3DL2 is peptide-specific

Persistence of Th1/Tc1 responses one year after tetravalent dengue vaccination in adults and adolescents in Singapore

NKp44 receptor mediates interaction of the envelope glycoproteins from the West Nile and dengue viruses with NK cells

Natural killer cells in dengue hemorrhagic fever/dengue shock syndrome

ACTH therapy in infantile spasms: relationship between dose of ACTH and initial effect or long-term prognosis

KIR/HLA interactions and pathogen immunity

KIR3DS1/L1 and HLA-BW4-80I are associated with HIV disease progression among HIV typical Progressors and longterm Nonprogressors

Control of human viral infections by natural killer cells

Interactions between NKG2x immunoreceptors and HLA-E ligands display overlapping affinities and thermodynamics

Genome-wide association study identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1

Lysis of dengue virus-infected cells by natural cell-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity

Killer cell immunoglobulinlike receptor gene associations with autoimmune and allergic diseases, recurrent spontaneous abortion, and neoplasms

Functional and biochemical analysis of CD16 antigen on natural killer cells and granulocytes

Antibody dependent cellular cytotoxicity in pre-secondary dengue virus serotype 3 (DV3) but not in DV2 infection plasma samples inversely correlated with viremia levels

Identification of the 2B4 molecule as a counterreceptor for CD48

Circulating levels of soluble MICB in infants with symptomatic primary dengue virus infections

The combination of Type I IFN, TNF-alpha, and cell surface receptor engagement with dendritic cells enables NK cells to overcome immune evasion by dengue virus

Primary vaccination with low dose live dengue 1 virus generates a proinflammatory, multifunctional T cell response in humans

Functional requirements for signaling through the stimulatory and inhibitory mouse NKR-P1 (CD161) NK cell receptors

Sequence variations in HCV core-derived epitopes Alter binding of KIR2DL3 to HLA-C *03:04 and modulate NK cell function

Crystal structure of the human P58 killer cell inhibitory receptor (KIR2DL3) specific for HLA-CW3-related MHC Class I

Signaling through CD38 induces NK cell activation

Human KIR repertoires: shaped by genetic diversity and evolution

Elucidating the role of T cells in protection against and pathogenesis of dengue virus infections

Existence of both inhibitory (p58) and activatory (p50) receptors for HLA-C molecules in human natural killer cells

Evaluation of KIR genes in recurrent miscarriage

X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells

Identification and molecular characterization of NKP30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells

Molecular cloning of NKP46: a novel member of the immunoglobulin superfamily involved in triggering of natural cytotoxicity

Association of HLA Class-I and inhibitory KIR genotypes in gabonese patients infected by chikungunya or dengue Type-2 viruses

Control of acute dengue virus infection by natural killer cells

Longitudinal analysis of natural killer cells in dengue virus-infected patients in comparison to chikungunya and chikungunya/dengue virus-infected patients

CD56bright natural killer (NK) cells: an important NK cell subset

CD161 (human NKR-P1A) signaling in NK cells involves the activation of acid sphingomyelinase

KIR2DL4 (CD158D): an activation receptor for HLA-G

Associations of killer cell immunoglobulin-like receptor genes with rheumatoid arthritis

Interplay of natural killer cells and their receptors with the adaptive immune response

Immunity to dengue virus: a tale of original antigenic sin and tropical cytokine storms

Analysis of cell-mediated immune responses in support of dengue vaccine development efforts

CD38 triggers cytotoxic responses in activated human natural killer cells

The presence of KIR2DS5 confers protection against adult immune thrombocytopenia

Inhibition of ERK and proliferation in NK cell lines by soluble HLA-E released from Japanese encephalitis virus infected cells

Leukocyte immunoglobulin-like receptors as new players in autoimmunity

Distinct activation phenotype of a highly conserved novel HLA-B57-restricted epitope during dengue virus infection

Interaction of a dengue virus NS1-derived peptide with the inhibitory receptor KIR3DL1 on natural killer cells

Killer cell immunoglobulinlike receptor 3DL1-mediated recognition of human leukocyte antigen B

Natural killer cells act as rheostats modulating antiviral T cells

The human CD8+ T cell responses induced by a live attenuated tetravalent dengue vaccine are directed against highly conserved epitopes

NK cells controlling virus-specific T cells: rheostats for acute vs. persistent infections

Genetic variants of MICB and PLCE1 and associations with non-severe dengue

KIR3DL2 binds to HLA-B27 dimers and free H chains more strongly than other HLA class I and promotes the expansion of T cells in ankylosing spondylitis

Upregulation of MHC class I expression following dengue virus infection: the mechanism at the promoter level