Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent COVID-19 patients

AbstractCOVID-19 is an ongoing global crisis in which the development of effective vaccines and therapeutics will depend critically on understanding the natural immunity to the virus, including the role of SARS-CoV-2-specific T cells. We have conducted a study of 42 patients following recovery from COVID-19, including 28 mild and 14 severe cases, comparing their T cell responses to those of 16 control donors. We assessed the immune memory of T cell responses using IFNγ based assays with overlapping peptides spanning SARS-CoV-2 apart from ORF1. We found the breadth, magnitude and frequency of memory T cell responses from COVID-19 were significantly higher in severe compared to mild COVID-19 cases, and this effect was most marked in response to spike, membrane, and ORF3a proteins. Total and spike-specific T cell responses correlated with the anti-Spike, anti-Receptor Binding Domain (RBD) as well as anti-Nucleoprotein (NP) endpoint antibody titre (p<0.001, <0.001 and =0.002). We identified 39 separate peptides containing CD4+ and/or CD8+ epitopes, which strikingly included six immunodominant epitope clusters targeted by T cells in many donors, including 3 clusters in spike (recognised by 29%, 24%, 18% donors), two in the membrane protein (M, 32%, 47%) and one in the nucleoprotein (Np, 35%). CD8+ responses were further defined for their HLA restriction, including B*4001-restricted T cells showing central memory and effector memory phenotype. In mild cases, higher frequencies of multi-cytokine producing M- and NP-specific CD8+ T cells than spike-specific CD8+ T cells were observed. They furthermore showed a higher ratio of SARS-CoV-2-specific CD8+ to CD4+ T cell responses. Immunodominant epitope clusters and peptides containing T cell epitopes identified in this study will provide critical tools to study the role of virus-specific T cells in control and resolution of SARS-CoV-2 infections. The identification of T cell specificity and functionality associated with milder disease, highlights the potential importance of including non-spike proteins within future COVID-19 vaccine design.

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Detection of IFNγ-Secreting CD4+ and CD8+ Memory T Cells in COVID-19 Convalescents after Stimulation of Peripheral Blood Mononuclear Cells with Live SARS-CoV-2

Viruses ◽

10.3390/v13081490 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1490

Author(s):

Victoria Matyushenko ◽

Irina Isakova-Sivak ◽

Igor Kudryavtsev ◽

Arina Goshina ◽

Anna Chistyakova ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Memory T Cells ◽

Natural Infection ◽

Intracellular Cytokine Staining ◽

T Cell Responses ◽

Effector Memory ◽

Memory T Cell ◽

Cell Responses ◽

Stimulation Of

Background: New coronavirus SARS-CoV-2, a causative agent of the COVID-19 pandemic, has been circulating among humans since November 2019. Multiple studies have assessed the qualitative and quantitative characteristics of virus-specific immunity in COVID-19 convalescents, however, some aspects of the development of memory T-cell responses after natural SARS-CoV-2 infection remain uncovered. Methods: In most of published studies T-cell immunity to the new coronavirus is assessed using peptides corresponding to SARS-CoV-1 or SARS-CoV-2 T-cell epitopes, or with peptide pools covering various parts of the viral proteins. Here, we determined the level of CD4+ and CD8+ memory T-cell responses in COVID-19 convalescents by stimulating PBMCs collected 1 to 6 months after recovery with sucrose gradient-purified live SARS-CoV-2. IFNγ production by the central and effector memory helper and cytotoxic T cells was assessed by intracellular cytokine staining assay and flow cytometry. Results: Stimulation of PBMCs with live SARS-CoV-2 revealed IFNγ-producing T-helper effector memory cells with CD4+CD45RA−CCR7− phenotype, which persisted in circulation for up to 6 month after COVID-19. In contrast, SARS-CoV-2-specific IFNγ-secreting cytotoxic effector memory T cells were found at significant levels only shortly after the disease, but rapidly decreased over time. Conclusion: The stimulation of immune cells with live SARS-CoV-2 revealed a rapid decline in the pool of effector memory CD8+, but not CD4+, T cells after recovery from COVID-19. These data provide additional information on the development and persistence of cellular immune responses after natural infection, and can inform further development of T cell-based SARS-CoV-2 vaccines.

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Protection against Vaccinia Virus Challenge by CD8 Memory T Cells Resolved by Molecular Mimicry

Journal of Virology ◽

10.1128/jvi.01280-06 ◽

2006 ◽

Vol 81 (2) ◽

pp. 934-944 ◽

Cited By ~ 28

Author(s):

Markus Cornberg ◽

Brian S. Sheridan ◽

Frances M. Saccoccio ◽

Michael A. Brehm ◽

Liisa K. Selin

Keyword(s):

T Cells ◽

T Cell ◽

Vaccinia Virus ◽

Cd8 T Cells ◽

Protective Immunity ◽

Molecular Mimicry ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Epitopes ◽

Cell Responses

ABSTRACT Live vaccinia virus (VV) vaccination has been highly successful in eradicating smallpox. However, the mechanisms of immunity involved in mediating this protective effect are still poorly understood, and the roles of CD8 T-cell responses in primary and secondary VV infections are not clearly identified. By applying the concept of molecular mimicry to identify potential CD8 T-cell epitopes that stimulate cross-reactive T cells specific to lymphocytic choriomeningitis virus (LCMV) and VV, we identified after screening only 115 peptides two VV-specific immunogenic epitopes that mediated protective immunity against VV. An immunodominant epitope, VV-e7r130, did not generate cross-reactive T-cell responses to LCMV, and a subdominant epitope, VV-a11r198, did generate cross-reactive responses to LCMV. Infection with VV induced strong epitope-specific responses which were stable into long-term memory and peaked at the time virus was cleared, consistent with CD8 T cells assisting in the control of VV. Two different approaches, direct adoptive transfer of VV-e7r-specific CD8 T cells and prior immunization with a VV-e7r-expressing ubiquitinated minigene, demonstrated that memory CD8 T cells alone could play a significant role in protective immunity against VV. These studies suggest that exploiting cross-reactive responses between viruses may be a useful tool to complement existing technology in predicting immunogenic epitopes to large viruses, such as VV, leading to a better understanding of the role CD8 T cells play during these viral infections.

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Pre-existing T cell memory against Zika virus

Journal of Virology ◽

10.1128/jvi.00132-21 ◽

2021 ◽

Author(s):

Blake Schouest ◽

Alba Grifoni ◽

John Pham ◽

Jose Mateus ◽

John Sydney ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Zika Virus ◽

Sequence Similarity ◽

T Cell Responses ◽

Natural Immunity ◽

Zikv Infection ◽

Cell Responses ◽

Cell Immunity ◽

Endemic Areas

The mosquito-borne Zika virus (ZIKV) spread rapidly into regions where dengue virus (DENV) is endemic, and flavivirus cross-reactive T cell responses have been observed repeatedly in animal models and in humans. Pre-existing cellular immunity to DENV is thought to contribute to protection in subsequent ZIKV infection, but the epitope targets of cross-reactive T cell responses have not been comprehensively identified. Using human blood samples from the DENV-endemic regions of Nicaragua and Sri Lanka that were collected before the global spread of ZIKV in 2016, we employed an in vitro expansion strategy to map ZIKV T cell epitopes in ZIKV-unexposed, DENV-seropositive donors. We identified 93 epitopes across the ZIKV proteome, and we observed patterns of immunodominance that were dependent on antigen size and sequence identity to DENV. We confirmed the immunogenicity of these epitopes through a computational HLA binding analysis, and we showed that cross-reactive T cells specifically recognize ZIKV peptides homologous to DENV sequences. We also found that these CD4 responses were derived from the memory T cell compartment. These data have implications for understanding the dynamics of flavivirus-specific T cell immunity in endemic areas. Importance Multiple flaviviruses, including Zika (ZIKV) and the four serotypes of dengue (DENV) viruses, are prevalent in the same large tropical and equatorial areas inhabited by hundreds of millions of people. The interplay of DENV and ZIKV infection is especially relevant, as these two viruses are endemic in largely overlapping regions, have significant sequence similarity, and share the same arthropod vector. Here, we define the targets of pre-existing immunity to ZIKV in unexposed subjects collected in dengue-endemic areas. We demonstrate that pre-existing immunity to DENV could shape ZIKV-specific responses, and DENV-ZIKV cross-reactive T cells can be expanded by stimulation with ZIKV peptides. The issue of potential ZIKV and DENV cross-reactivity is of relevance for understanding patterns of natural immunity, as well as for the development of diagnostic tests and vaccines.

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Vaccinia-specific cytotoxic T-cell responses in the context of H-2 antigens not encountered in thymus may reflect aberrant recognition of a virus-H-2 complex.

Journal of Experimental Medicine ◽

10.1084/jem.149.1.150 ◽

1979 ◽

Vol 149 (1) ◽

pp. 150-157 ◽

Cited By ~ 56

Author(s):

P C Doherty ◽

J C Bennink

Keyword(s):

T Cells ◽

T Cell ◽

Vaccinia Virus ◽

T Cell Responses ◽

Cytotoxic T Cell ◽

Cell Responses ◽

Antigen Complex ◽

Infected Cells ◽

Cytotoxic T Cell Responses

BALB/c (H-2Kd-Dd) spleen and lymph node populations were specifically depleted of alloreactive potential by filtration through H-2 different, irradiated recipients. These negatively selected T cells were then stimulated with vaccinia virus in mice expressing the foreign H-2 determinants encountered previously in the filter environment. Strong virus-immune cytotoxic T-cell responses were seen in the context of H-2Kk and H-2Ks, but not 2H-2Kb. The T cells generated were not cross-reactive for the H-2Kk and H-2Kd alleles, and responsiveness was independent of concurrent presence of effector populations operating at H-2D. These findings are consisent with the idea that recognition is mediated via a complex receptor, part of which is specific for virus and part for self H-2. The capacity to interact with allogeneic, virus-infected cells may then reflect aberrant recognition of a virus-H-2-antigen complex by this single, large binding site. For instance, the T cell which would normally recognize H-2Kd-virus x, or H-2Dd-minor histocompatibility antigen Z, may now show specificity for H-2Kk-vaccinia virus. Implications for both the selective role of the thymus and for mechanisms of tolerance are discussed.

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Optimising T cell (re)boosting strategies for adenoviral and modified vaccinia Ankara vaccine regimens in humans

npj Vaccines ◽

10.1038/s41541-020-00240-0 ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Stefania Capone ◽

Anthony Brown ◽

Felicity Hartnell ◽

Mariarosaria Del Sorbo ◽

Cinzia Traboni ◽

...

Keyword(s):

T Cells ◽

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

Viral Vectors ◽

Standard Dose ◽

T Cell Responses ◽

Effector Memory ◽

Cell Responses ◽

Wide Range

Abstract Simian adenoviral and modified vaccinia Ankara (MVA) viral vectors used in heterologous prime-boost strategies are potent inducers of T cells against encoded antigens and are in advanced testing as vaccine carriers for a wide range of infectious agents and cancers. It is unclear if these responses can be further enhanced or sustained with reboosting strategies. Furthermore, despite the challenges involved in MVA manufacture dose de-escalation has not been performed in humans. In this study, healthy volunteers received chimpanzee-derived adenovirus-3 and MVA vaccines encoding the non-structural region of hepatitis C virus (ChAd3-NSmut/MVA-NSmut) 8 weeks apart. Volunteers were then reboosted with a second round of ChAd3-NSmut/MVA-NSmut or MVA-NSmut vaccines 8 weeks or 1-year later. We also determined the capacity of reduced doses of MVA-NSmut to boost ChAd3-NSmut primed T cells. Reboosting was safe, with no enhanced reactogenicity. Reboosting after an 8-week interval led to minimal re-expansion of transgene-specific T cells. However, after a longer interval, T cell responses expanded efficiently and memory responses were enhanced. The 8-week interval regimen induced a higher percentage of terminally differentiated and effector memory T cells. Reboosting with MVA-NSmut alone was as effective as with ChAd3-NSmut/MVA-NSmut. A ten-fold lower dose of MVA (2 × 107pfu) induced high-magnitude, sustained, broad, and functional Hepatitis C virus (HCV)-specific T cell responses, equivalent to standard doses (2 × 108 pfu). Overall, we show that following Ad/MVA prime-boost vaccination reboosting is most effective after a prolonged interval and is productive with MVA alone. Importantly, we also show that a ten-fold lower dose of MVA is as potent in humans as the standard dose.

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Lymphocytic Choriomeningitis Virus Infection Yields Overlapping CD4+ and CD8+ T-Cell Responses

Journal of Virology ◽

10.1128/jvi.00435-08 ◽

2008 ◽

Vol 82 (23) ◽

pp. 11734-11741 ◽

Cited By ~ 27

Author(s):

Courtney Dow ◽

Carla Oseroff ◽

Bjoern Peters ◽

Courtney Nance-Sotelo ◽

John Sidney ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Intracellular Cytokine Staining ◽

T Cell Responses ◽

Lymphocytic Choriomeningitis ◽

Lymphocytic Choriomeningitis Virus ◽

T Cell Epitopes ◽

Binding Assays ◽

Cell Responses ◽

Lymphocytic Choriomeningitis Virus Infection

ABSTRACT Activation of CD4+ T cells helps establish and sustain other immune responses. We have previously shown that responses against a broad set of nine CD4+ T-cell epitopes were present in the setting of lymphocytic choriomeningitis virus (LCMV) Armstrong infection in the context of H-2d. This is quite disparate to the H-2b setting, where only two epitopes have been identified. We were interested in determining whether a broad set of responses was unique to H-2d or whether additional CD4+ T-cell epitopes could be identified in the setting of the H-2b background. To pursue this question, we infected C57BL/6 mice with LCMV Armstrong and determined the repertoire of CD4+ T-cell responses using overlapping 15-mer peptides corresponding to the LCMV Armstrong sequence. We confirmed positive responses by intracellular cytokine staining and major histocompatibility complex (MHC)-peptide binding assays. A broad repertoire of responses was identified, consisting of six epitopes. These epitopes originate from the nucleoprotein (NP) and glycoprotein (GP). Out of the six newly identified CD4+ epitopes, four of them also stimulate CD8+ T cells in a statistically significant manner. Furthermore, we assessed these CD4+ T-cell responses during the memory phase of LCMV Armstrong infection and after infection with a chronic strain of LCMV and determined that a subset of the responses could be detected under these different conditions. This is the first example of a broad repertoire of shared epitopes between CD4+ and CD8+ T cells in the context of viral infection. These findings demonstrate that immunodominance is a complex phenomenon in the context of helper responses.

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Characterization of local and circulating bovine γδ T cell responses to respiratory BCG vaccination

Scientific Reports ◽

10.1038/s41598-019-52565-z ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Mariana Guerra-Maupome ◽

Jodi L. McGill

Keyword(s):

T Cells ◽

T Cell ◽

Γδ T Cells ◽

T Cell Responses ◽

Memory Cell ◽

Effector Memory ◽

Γδ T Cell ◽

Respiratory Mucosa ◽

Bcg Vaccination ◽

Cell Responses

Abstract The Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccine is administered parenterally to infants and young children to prevent tuberculosis (TB) infection. However, the protection induced by BCG is highly variable and the vaccine does not prevent pulmonary TB, the most common form of the illness. Until improved TB vaccines are available, it is crucial to use BCG in a manner which ensures optimal vaccine performance. Immunization directly to the respiratory mucosa has been shown to promote greater protection from TB in animal models. γδ T cells play a major role in host defense at mucosal sites and are known to respond robustly to mycobacterial infection. Their positioning in the respiratory mucosa ensures their engagement in the response to aerosolized TB vaccination. However, our understanding of the effect of respiratory BCG vaccination on γδ T cell responses in the lung is unknown. In this study, we used a calf model to investigate the immunogenicity of aerosol BCG vaccination, and the phenotypic profile of peripheral and mucosal γδ T cells responding to vaccination. We observed robust local and systemic M. bovis-specific IFN-γ and IL-17 production by both γδ and CD4 T cells. Importantly, BCG vaccination induced effector and memory cell differentiation of γδ T cells in both the lower airways and peripheral blood, with accumulation of a large proportion of effector memory γδ T cells in both compartments. Our results demonstrate the potential of the neonatal calf model to evaluate TB vaccine candidates that are to be administered via the respiratory tract, and suggest that aerosol immunization is a promising strategy for engaging γδ T cells in vaccine-induced immunity against TB.

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130 Immunogenic potential of chimeric antigen receptor (CAR)-engineered T cells expressing inducible nuclease-deactivated SpCas9 (dCas9)

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0130 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A143-A143

Author(s):

Dharmeshkumar Patel ◽

Angshumala Goswami ◽

Vitaly Balan ◽

Zhifen Yang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Peptide Sequence ◽

T Cell Epitopes ◽

Cell Responses ◽

Car T Cells ◽

Car T

BackgroundThe application of CRISPR-Cas9 for personalized medicine is potentially revolutionary for the treatment of several diseases including cancer. However, the bacterial origin of the Cas9 protein raises concerns about immunogenicity. Recent ELISA-based assays detected antibodies against Cas9 from Streptococcus pyogenes (SpCas9) and Staphylococcus aureus (SaCas9) in 5–10% of sera from 343 normal healthy individuals.1,2 SpCas9-specific memory CD8 T cell responses were not demonstrated in those individuals. To date, there are no conclusive studies assessing whether CRISPR-Cas9-modified CAR-T could raise CD8 T cell-mediated immunogenicity in humans. Refuge CAR-T cell platform employs an inducible, non-gene editing, nuclease deactivated Cas9 (dCas9) to modulate gene expression in response to external stimuli such as antigen-dependent CAR signaling to suppress PD-1 expression.MethodsIn the present study, we analyzed two putative HLA-A*02:01 and two HLA-B*07:02-associated SpCas9 T cell epitopes. The candidate epitopes were derived from a prediction algorithm that incorporates T cell receptor contact residue hydrophobicity and HLA binding affinity. We engaged in-vitro sensitization (IVS) assay to identify immunogenic potential of dCas9 peptides.ResultsAutologous IVS assay of T cells in two healthy donor PBMCs identified CD8-T cell responses after two rounds of stimulation against only one HLA-A*02:01-associated Cas9 peptide (sequence NLIALSLGL) P1– while the other candidate epitopes did not elicit any response. Dextramer analysis demonstrated that 15% of CD8+ T cells were specific for P1 and ~11% of CD8+ cells produced INFG upon challenge with P1-loaded T2 cells.ConclusionsOur in-vitro sensitization assay was able to demonstrate that dCas9 epitope P1 is immunogenic and may elicit adaptive immune response against gene edited CAR-T cells. Endogenous processing and presentation of P1 and other putative epitopes by Refuge CAR-T cells are currently being analyzed.AcknowledgementsRefuge Biotechnologies Inc. Menlo Park, California, 94025Trial RegistrationN/AEthics ApprovalN/AConsentN/AReferencesSimhadri VL, McGill J, McMahon S, Wang J, Jiang H, Sauna ZE. Prevalence of Pre-existing Antibodies to CRISPR-Associated Nuclease Cas9 in the USA Population. Mol Ther Methods Clin Dev 2018;10:105–112. Published 2018 Jun 15. doi:10.1016/j.omtm.2018.06.006Ferdosi SR, Ewaisha R, Moghadam F, et al. Multifunctional CRISPR-Cas9 with engineered immunosilenced human T cell epitopes. Nat Commun2019;10(1):1842. Published 2019 Apr 23. doi:10.1038/s41467-019-09693-x

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HIV-1 Antibody Neutralization Breadth Is Associated with Enhanced HIV-Specific CD4+T Cell Responses

Journal of Virology ◽

10.1128/jvi.02278-15 ◽

2015 ◽

Vol 90 (5) ◽

pp. 2208-2220 ◽

Cited By ~ 22

Author(s):

Srinika Ranasinghe ◽

Damien Z. Soghoian ◽

Madelene Lindqvist ◽

Musie Ghebremichael ◽

Faith Donaghey ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Hiv Infection ◽

Neutralizing Antibodies ◽

T Cell Responses ◽

Neutralizing Antibody ◽

Antibody Activity ◽

Cell Responses

ABSTRACTAntigen-specific CD4+T helper cell responses have long been recognized to be a critical component of effective vaccine immunity. CD4+T cells are necessary to generate and maintain humoral immune responses by providing help to antigen-specific B cells for the production of antibodies. In HIV infection, CD4+T cells are thought to be necessary for the induction of Env-specific broadly neutralizing antibodies. However, few studies have investigated the role of HIV-specific CD4+T cells in association with HIV neutralizing antibody activity in vaccination or natural infection settings. Here, we conducted a comprehensive analysis of HIV-specific CD4+T cell responses in a cohort of 34 untreated HIV-infected controllers matched for viral load, with and without neutralizing antibody breadth to a panel of viral strains. Our results show that the breadth and magnitude of Gag-specific CD4+T cell responses were significantly higher in individuals with neutralizing antibodies than in those without neutralizing antibodies. The breadth of Gag-specific CD4+T cell responses was positively correlated with the breadth of neutralizing antibody activity. Furthermore, the breadth and magnitude of gp41-specific, but not gp120-specific, CD4+T cell responses were significantly elevated in individuals with neutralizing antibodies. Together, these data suggest that robust Gag-specific CD4+T cells and, to a lesser extent, gp41-specific CD4+T cells may provide important intermolecular help to Env-specific B cells that promote the generation or maintenance of Env-specific neutralizing antibodies.IMPORTANCEOne of the earliest discoveries related to CD4+T cell function was their provision of help to B cells in the development of antibody responses. Yet little is known about the role of CD4+T helper responses in the setting of HIV infection, and no studies to date have evaluated the impact of HIV-specific CD4+T cells on the generation of antibodies that can neutralize multiple different strains of HIV. Here, we addressed this question by analyzing HIV-specific CD4+T cell responses in untreated HIV-infected persons with and without neutralizing antibodies. Our results indicate that HIV-infected persons with neutralizing antibodies have significantly more robust CD4+T cell responses targeting Gag and gp41 proteins than individuals who lack neutralizing antibodies. These associations suggest that Gag- and gp41-specific CD4+T cell responses may provide robust help to B cells for the generation or maintenance of neutralizing antibodies in natural HIV-infection.

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NKp80 defines and stimulates a reactive subset of CD8 T cells

Blood ◽

10.1182/blood-2008-03-145615 ◽

2009 ◽

Vol 113 (2) ◽

pp. 358-369 ◽

Cited By ~ 32

Author(s):

Sabrina Kuttruff ◽

Sven Koch ◽

Alexandra Kelp ◽

Graham Pawelec ◽

Hans-Georg Rammensee ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Natural Killer ◽

Cd8 T Cells ◽

Cell Subset ◽

T Cell Responses ◽

Effector Memory ◽

Memory Cd8 T Cells ◽

Cell Responses ◽

Natural Killer Gene Complex

Abstract NKp80, an activating homodimeric C-type lectin-like receptor (CTLR), is expressed on essentially all human natural killer (NK) cells and stimulates their cytotoxicity and cytokine release. Recently, we demonstrated that the ligand for NKp80 is the myeloid-specific CTLR activation-induced C-type lectin (AICL), which is encoded in the natural killer gene complex (NKC) adjacent to NKp80. Here, we show that NKp80 also is expressed on a minor fraction of human CD8 T cells that exhibit a high responsiveness and an effector memory phenotype. Gene expression profiling and flow cytometric analyses revealed that this NKp80+ T-cell subset is characterized by the coexpression of other NK receptors and increased levels of cytotoxic effector molecules and adhesion molecules mediating access to sites of inflammation. NKp80 ligation augmented CD3-stimulated degranulation and interferon (IFN)γ secretion by effector memory T cells. Furthermore, engagement of NKp80 by AICL-expressing transfectants or macrophages markedly enhanced CD8 T-cell responses in alloreactive settings. Collectively, our data demonstrate that NKp80 is expressed on a highly responsive subset of effector memory CD8 T cells with an inflammatory NK-like phenotype and promotes T-cell responses toward AICL-expressing cells. Hence, NKp80 may enable effector memory CD8 T cells to interact functionally with cells of myeloid origin at sites of inflammation.

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