key: cord-0934587-4cot16k9
authors: Kedzierska, Katherine; Thomas, Paul G.
title: Count on us: T-cells in SARS-CoV-2 infection and vaccination
date: 2022-02-25
journal: Cell Rep Med
DOI: 10.1016/j.xcrm.2022.100562
sha: 262fa5f8f33c90cbc7a8033db0a53ee079040287
doc_id: 934587
cord_uid: 4cot16k9

Robust T-cell responses have been associated with milder outcomes in many infections. T-cells also establish long-term memory pools and, as they are predominantly directed towards epitopes encompassing conserved peptides, can respond to SARS-CoV-2 variants, including Omicron. Here, we discuss epitope-specific CD8+ and CD4+ T-cell responses towards SARS-CoV-2 infection and vaccination, their subsequent persistence into long-term memory, and ongoing work to determine their role in limiting disease severity.

Robust T-cell responses have been associated with milder outcomes in many infections. T-20 cells also establish long-term memory pools and, as they are predominantly directed towards 21 epitopes encompassing conserved peptides, can respond to SARS-CoV-2 variants, 22

including Omicron. Here, we discuss epitope-specific CD8 + and CD4 + T-cell responses 23 towards SARS-CoV-2 infection and vaccination, their subsequent persistence into long-term 24 memory, and ongoing work to determine their role in limiting disease severity. Two years since SARS-CoV-2 emerged in China, the virus has spread rapidly, causing the 31 coronavirus disease 2019 pandemic with >400 million infections and >5.7 32 million deaths. Infection with SARS-CoV-2 results in a spectrum of clinical presentations, 33 ranging from asymptomatic to mild, severe, and fatal disease. Severe and fatal disease 34 outcomes are predominantly associated with risk factors including age and pre-existing neutralising antibodies, can generate sterilising immunity and prevent SARS-CoV-2 infection 43 4 , it is hypothesized that T-cells can limit disease severity, reduce its duration and drive rapid 44 recovery. While some have reported correlations between T-cell responses and disease 45 severity, these studies are limited compared to the extensive work demonstrating a protective 46 role for antibodies. Indeed, a rigorous correlate of protection against severe disease based 47

on T-cell responses has not been demonstrated for SARS-CoV-2. The ongoing emergence 48 of new variants with greater capacity for antibody escape highlights the need for an expanded 49 understanding of protective roles played by T-cells, tools to assess them in the broader 50 population, and to identify those who may have poor T-cell memory. Memory T-cells may be 51

of key importance when antibody levels wane or new variants of concern emerge that escape 52 antibody responses. As T-cells are generally directed at epitopes encompassing conserved 53 viral regions, they can recognise emerging variants. We discuss T-cell responses towards 54 the pandemic SARS-CoV-2 infection and vaccination, focussing on conventional epitope-55 J o u r n a l P r e -p r o o f A3/N361, A24/S1208, B7/N105, and B40/N322) led to insights into CD8 + T-cell origins, magnitude, 109 phenotype and immunodominance hierarchies directly ex vivo 21 . The magnitude of SARS-110

CoV-2-specific CD8 + T-cells ex vivo during acute COVID-19 or early convalescence varies 111 broadly, across a range of 10 -5 to as high as 10 -1 in some individuals for certain epitopes 23 . 112 CD8 + T-cells directed at the HLA-B*07:02-restricted N105-113 (B7/N105 + CD8 + T-cells) are 113 among the more immunodominant SARS-CoV-2 CD8 + T-cell responses identified to date 114 9,21,22 . The immunodominance of B7/N105 + CD8 + T-cells over other CD8 + T-cell sets, including 115 B7/N257 + CD8 + , A2/S269 + CD8 + , A24/S1208 + CD8 + T-cells, was underpinned by high naïve 116 precursor frequencies in pre-pandemic children, adult and elderly samples. Such high 117 numbers of B7/N105 + CD8 + naïve precursors stemmed from highly diverse TCR repertoire 118 arisen from plasticity in TCR-TCR pairing and lack of common TRAV, TRAJ, TRBV or 119 TRBJ gene segments 21 . Importantly, robust B7/N105 + CD8 + T-cell responses characterised 120 by expanded TCR clones with high functional avidity and anti-viral effector functions were 121 found in patients with mild COVID-19 disease outcomes, while patients who recovered from 122 severe disease had weaker B7/N105 + CD8 + T-cell responses 9 , suggesting that B7/N105 + CD8 + 123 T-cells contribute to SARS-CoV-2 control. Prominent B7/N105 + CD8 + T-cell populations 124 responded to the ancestral strain and variants of concern, including the delta strain. These 125 findings support previous studies in animals and humans that TCR repertoire diversity plays 126 a key role in selection of high avidity CD8 + T-cell responses important for protection from 127 viral infections against both the wild-type virus and viral variants. 128

Conversely, CD8 + T-cells directed at the HLA-A*02:01-restricted S269-277 epitope 129 (A2/S269), although immunodominant across known SARS-CoV-2-specific HLA-A*02:01-130 restricted epitopes, are numerically subdominant when compared to B7/N105 + CD8 + T-cells 131 15,21 . This stems from a biased TCR repertoire displaying common TRBV gene segments 132 within A2/S269 + CD8 + T-cells (TRBV2/TRBV7-9/TRBV20-1), TRBJ (TRBJ2-2/TRBJ2-7), 133 TRAV (TRAV12-1/TRAV12-2/TRAV14/DV4) and TRAJ (TRAJ43/TRAJ30). The molecular 134 basis underlying biased TRAV12-mediated recognition of A2/S269 was defined by solving a 135 J o u r n a l P r e -p r o o f ternary structure of TRAV12 + TCR complexed with A2/S269 24 , which found that the TRAV12 + 136 TCR docked atop HLA-A*02:01, with both TRAV12 germline-encoded residues and amino 137 acids derived from conserved CDR3 and CDR3 motifs playing a key role in A2/S269 138

While SARS-CoV-2-specific CD8 + T-cell epitopes restricted by predominant HLA-I are 140

known, CD4 + T-cell epitopes have been understudied, with fewer epitopes identified, in part 141 due to the limitations in reagents for Class-II multimers. As a result, rather than strictly 142 phenotypes should be carefully examined to ensure that they are retaining potency (Fig.1) . 186

For CD4 + T-cells, the BNT162b2 vaccine induces robust tetramer-specific CD4 + T-cell 187 responses directed at the prominent DPB1*04/S166-180 epitope in peripheral blood and lymph 188 nodes 27 . DPB1*04/S166-180 + CD4 + T-cells were detected at day 21 after the first vaccine dose, 189 J o u r n a l P r e -p r o o f peaked at 7 days following the second dose, displayed a primarily CCR7 -CD45RAeffector 190 memory phenotype and persisted for >200 days. Tetramer-specific Tfh were detected in 191 blood as circulating Tfh DPB1*04/S167-180 + CXCR5 + PD1 + cells and in lymph nodes at 30 days 

T-cell responses appear to contract at slower rate than IgG antibodies during the first few Overall, data on SARS-CoV-2-specific CD4 + and CD8 + T-cells clearly demonstrate 231 generation of long-term immunological epitope-specific memory T-cell pools following 232

BNT162b2 mRNA COVID-19 vaccination. 233 234

Memory T-cells established either by infection, vaccination or a hybrid infection/vaccination, 236

can respond to SARS-CoV-2 and variants of concern 40 . Viral peptides within dominant CD8 + 237 and CD4 + T-cell epitopes described in this commentary are conserved within the variants of 238 concern and can respond to delta and omicron strains, as exemplified by B7/N105 + CD8 + T- of the world's population has pre-existing T-cells to Omicron, some individuals present non-263 conserved peptides and hence have limited T-cell immunity to Omicron. 264 It is important to note that thus far, studies assessing responsiveness to variants 265 primarily utilize peptide pools or multimer reagents to identify memory T-cell populations. An 266 understudied element of SARS-CoV-2 immunity is the extent to which antigen presentation 267 varies among variants and whether processing and presentation of specific epitopes might 268 be altered by mutations outside the minimal epitope. Furthermore, the virus, with its 269 extensive array of innate immune modulation, could affect general features of the processing 270 and presentation machinery and these mechanisms may differ across variants. Studies 271

detecting T-cell responses to infected cells directly will help address these considerations. 272

273

With the rapid spread of Omicron, even in previously vaccinated and boosted individuals, 275 many questions need to be answered regarding T-cell immunity. In particular, the extent to While a true T cell-based correlate of protection has not been defined, several studies 289 implicate T cells as protective based on associations with symptoms and outcomes 49, 50 . 290

These studies identify robust T cell responses in subjects with asymptomatic disease or low 291 symptom severity. In contrast, a number of studies have found that T cell responses in 292 severely ill subjects show evidence of dysregulation, dysfunction, or deletion 51-53 . These 293 studies indicate that failure of T cells to elicit productive control may drive them towards 294 pathological states that contribute to disease propagation without promoting viral clearance. 295

Indeed, early dysregulated T cell responses may be causal in this phenotype, forming a 296 vicious cycle whereby their initial failure to control infection drives further differentiation and 297 functional profiles that inflict tissue damage without effectively eliminating viral reservoirs. 298

As noted, in contrast to antibody correlates for SARS-CoV-2 and other viruses 54-57 , 299 no true T cell correlate of protection has been defined. To do so will require longitudinally 300 monitored cohorts with known exposure data, where antibody and T cell responses can be 301 integrated in models to capture their individual contributions. Ideally, these measures will 302 include features of T magnitude, specificity, and possibly function, though each parameter 303 increases the difficulty of assessment. 304 305

At 2 years of COVID-19 pandemic, remarkable progress has been made in terms of 307 understanding immune responses to SARS-CoV-2, developing and implementing vaccines. 308

As we strive to immunize the global population, new variants emerge. Following SARS-CoV-309 2 infection and vaccination, long-lived CD4 + and CD8 + T-cell memory pools are established, 310 capable of being recalled following subsequent SARS-CoV-2 infection, even against highly 311 drifted variants such as Omicron. So far, T-cell responses are not greatly affected by 312 emergence of variants of concern, thus can provide pre-existing immunity for the variants. 

Humoral and circulating follicular helper T cell 339 responses in recovered patients with COVID-19

Integrated immune dynamics define 342 correlates of COVID-19 severity and antibody responses

Breadth of concomitant immune responses 345 prior to patient recovery: a case report of non-severe COVID-19

Neutralizing antibody levels are highly 348 predictive of immune protection from symptomatic SARS-CoV-2 infection

Correlates of protection against SARS-CoV-2 in 352 rhesus macaques

T cell responses are required for protection from 354 clinical disease and for virus clearance in severe acute respiratory syndrome coronavirus-355 infected mice

Mapping and role of T cell response in SARS-CoV-2-infected mice

Immunopathological 360 characteristics of coronavirus disease

An immunodominant NP105-113-B*07:02 cytotoxic T cell response 364 controls viral replication and is associated with less severe COVID-19 disease

CD8+ T cells contribute to survival in 368 patients with COVID-19 and hematologic cancer

Coronavirus Disease 2019 Outcomes Among 371 Recipients of Anti-CD20 Monoclonal Antibodies for Immune-Mediated Diseases: A 372 Comparative Cohort Study. ACR Open Rheumatol

Targets of T Cell Responses to 375 SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals

SARS-CoV-2-specific T cell immunity in cases of 379 COVID-19 and SARS, and uninfected controls

Phenotype 382 and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory 383 distress syndrome

CD8+ T cell response associated with the prominent HLA-A*02:01 phenotype

Selective and cross-reactive SARS-CoV-2 T cell 390 epitopes in unexposed humans

Robust T Cell 393 Immunity in Convalescent Individuals with Asymptomatic or Mild COVID-19

Pre-existing polymerase-specific T cells 397 expand in abortive seronegative SARS-CoV-2

Exposure to SARS-CoV-2 generates T-cell memory in the absence of a detectable 400 viral infection

Cross-reactive memory T cells 403 associate with protection against SARS-CoV-2 infection in COVID-19 contacts

CD8+ T cells specific for an 407 immunodominant SARS-CoV-2 nucleocapsid epitope display high naive precursor frequency 408 and TCR promiscuity

Characterization of pre-existing and induced 411 SARS-CoV-2-specific CD8+ T cells

Identification and characterization of a 414 SARS-CoV-2 specific CD8+ T cell response with immunodominant features

Structural basis of biased T cell receptor 418 recognition of an immunodominant HLA-A2 epitope of the SARS-CoV-2 spike protein

Cross-reactive CD4+ T cells enhance SARS-CoV-2 422 immune responses upon infection and vaccination

Identification of conserved SARS-CoV-2 spike epitopes that 425 expand public cTfh clonotypes in mild COVID-19 patientsSARS-CoV-2 spike epitopes for 426 public cTfh cells

SARS-CoV-2 mRNA vaccination elicits a 429 robust and persistent T follicular helper cell response in humans

BNT162b2 vaccine induces neutralizing 432 antibodies and poly-specific T cells in humans

Safety, tolerability, and immunogenicity of a recombinant 435 adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, 436 first-in-human trial

SARS-CoV-2 vaccines in development

Convergent epitope-specific T cell responses 440 after SARS-CoV-2 infection and vaccination. medRxiv

Rapid and stable 443 mobilization of CD8+ T cells by SARS-CoV-2 mRNA vaccine

Circulating TFH cells, serological memory, and 446 tissue compartmentalization shape human influenza-specific B cell immunity

Rapid induction of antigen-specific 450

CD4+ T cells is associated with coordinated humoral and cellular immunity to SARS-CoV-2 451 mRNA vaccination

Prospects for durable immune control of SARS-CoV-2 and prevention of 454 reinfection

Immunogenicity of standard and extended 457 dosing intervals of BNT162b2 mRNA vaccine

Functional SARS-CoV-2-460 Specific Immune Memory Persists after Mild COVID-19

Robust SARS-CoV-2-specific T cell 463 immunity is maintained at 6 months following primary infection

Immunological memory to SARS-CoV-2 assessed for up to 466 8 months after infection

mRNA vaccines induce 469 durable immune memory to SARS-CoV-2 and variants of concern

Ancestral SARS-CoV-2-specific T cells cross-472 recognize the Omicron variant

Divergent 475 SARS CoV-2 Omicron-reactive T-and B cell responses in COVID-19 vaccine recipients

T cell responses to SARS-CoV-2 spike cross-recognize 479

Vaccines Elicit Highly Conserved Cellular 482 Immunity to SARS-CoV-2 Omicron

Preserved T cell reactivity to the SARS-485

CoV-2 Omicron variant indicates continued protection in vaccinated individuals

T-cell reactivity to the SARS-CoV-2 Omicron 489 variant is preserved in most but not all individuals

SARS-CoV-2 vaccination induces immunological T cell 492 memory able to cross-recognize variants from Alpha to Omicron

CoV-2 breakthrough infections in vaccinated individuals: measurement, causes and impact

Antigen-Specific Adaptive Immunity 499 to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity

Highly functional virus-specific cellular 503 immune response in asymptomatic SARS-CoV-2 infection

Longitudinal profiling of 506 respiratory and systemic immune responses reveals myeloid cell-driven lung inflammation in 507 severe COVID-19

Longitudinal analyses reveal immunological misfiring in 510 severe COVID-19

Imbalance of Regulatory and

CoV-2-Reactive CD4+ T Cells in COVID-19

An immune correlate of SARS-CoV-2 infection 516 and severity of reinfections. medRxiv

Immune correlates analysis of the 519 mRNA-1273 COVID-19 vaccine efficacy clinical trial

Correlates of protection against symptomatic and asymptomatic 522 SARS-CoV-2 infection

Association Between Hemagglutination Inhibition 525

Antibody Titers and Protection Against Reverse-Transcription Polymerase Chain Reaction-526

Confirmed Influenza Illness in Children 6-35 Months of Age: Statistical Evaluation of a 527 Correlate of Protection

-cell responses following SARS-CoV-2 infection and vaccination. They discuss epitope-specific T-cell responses during acute disease, persistence into long-term memory