scholarly journals Dimorphism in the TCRγ-chain repertoire defines 2 types of human immunity to Epstein-Barr virus

2020 ◽  
Vol 4 (7) ◽  
pp. 1198-1205 ◽  
Author(s):  
Zakia Djaoud ◽  
Peter Parham
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Nk Cell ◽  
Γδ T Cells ◽  
T Cell Response ◽  
Γδ T Cell ◽  
Barr Virus ◽  
Group 2 ◽  
Group 1

Abstract Humans form 2 groups based on their innate immunity to Epstein-Barr virus (EBV). Group 1 makes a strong natural killer (NK)–cell and γδ T-cell response, whereas group 2 makes a strong NK-cell response, but a weak γδ T-cell response. To investigate the underlying basis for this difference in γδ T-cell immunity to EBV, we used next-generation sequencing to compare the γδ T-cell receptor (TCR) repertoires of groups 1 and 2. In the absence of EBV, group 1 TCRγ chains are enriched for complementarity determining region 3 (CDR3s) containing JγP, whereas group 2 TCRγ chains are enriched for CDR3s containing Jγ2. In group 1 donors, EBV activates many γδ T cells expressing Vγ9JγP, inducing proliferation that produces a large population of activated effector cells. The TCRs using Vγ9JγP are closely related to the TCRs of γδ T cells that respond to phosphoantigens. In group 2 donors, EBV activates a small subpopulation of γδ T cells, most expressing Vγ9JγP. In conclusion, we find that differences in the TCRγ-chain repertoire underlie the differential response of group 1 and group 2 to EBV.

scholarly journals The role of antigen recognition in the γδ T cell response at the controlled stage of M. tuberculosis infection.

2021 ◽  
Author(s):  
Roshni Roy Chowdhury ◽  
John R Valainis ◽  
Oliver Kask ◽  
Mane Ohanyan ◽  
Meng Sun ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Specific Antigen ◽  
Γδ T Cells ◽  
T Cell Response ◽  
Immune Defense ◽  
Γδ T Cell ◽  
Antigenic Exposure

γδ T cells contribute to host immune defense uniquely; but how they function in different stages (e.g., acute versus chronic) of a specific infection remains unclear. As the role of γδ T cells in early, active Mycobacterium tuberculosis (Mtb) infection is well documented, we focused on elucidating the γδ T cell response in persistent or controlled Mtb infection. Systems analysis of circulating gd T cells from a South African adolescent cohort identified a distinct population of CD8+ γδ T cells that expanded in this state. These cells had features indicative of persistent antigenic exposure but were robust cytolytic effectors and cytokine/chemokine producers. While these γδ T cells displayed an attenuated response to TCR-mediated stimulation, they expressed Natural Killer (NK) cell receptors and had robust CD16 (FcgRIIIA)-mediated cytotoxic response, suggesting alternative ways for gd T cells to control this stage of the infection. Despite this NK-like functionality, the CD8+ γδ T cells consisted of highly expanded clones, which utilized TCRs with different Vg/d pairs. Theses TCRs could respond to an Mtb-lysate, but not to phosphoantigens, which are components of Mtb-lysate that activate gd T cells in acute Mtb infection, indicating that the CD8+ γδ T cells were induced in a stage-specific, antigen-driven manner. Indeed, trajectory analysis showed that these γδ T cells arose from naive cells that had traversed distinct differentiation paths in this infection stage. Importantly, increased levels of CD8+ γδ T cells were also found in other chronic inflammatory conditions, including cardiovascular disease and cancer, suggesting that persistent antigenic exposure may lead to similar γδ T cell responses.

Deciphering human γδ T cell response in cancer: Lessons from tumor‐infiltrating γδ T cells

2020 ◽  
Vol 298 (1) ◽  
pp. 153-164
Author(s):  
Elena Lo Presti ◽  
Francesco Dieli ◽  
Jean Jacques Fourniè ◽  
Serena Meraviglia
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Γδ T Cells ◽  
T Cell Response ◽  
Γδ T Cell

scholarly journals IL-21 inhibits IL-17A-producing γδ T-cell response after infection with Bacillus Calmette-Guérin via induction of apoptosis

2016 ◽  
Vol 22 (8) ◽  
pp. 588-597 ◽  
Author(s):  
Yinxia Huang ◽  
Yumiko Matsumura ◽  
Shinya Hatano ◽  
Naoto Noguchi ◽  
Tesshin Murakami ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Early Stage ◽  
Cell Subset ◽  
Γδ T Cells ◽  
T Cell Response ◽  
Bacillus Calmette Guerin ◽  
Γδ T Cell ◽  
Induced Apoptosis

Innate γδ T cells expressing Vγ6 produce IL-17A at an early stage following infection with Mycobacterium bovis Bacillus Calmette-Guérin (BCG). In this study, we used IL-21 receptor knockout (IL-21R KO) mice and IL-21-producing recombinant BCG mice (rBCG-Ag85B-IL-21) to examine the role of IL-21 in the regulation of IL-17A-producing innate γδ T-cell response following BCG infection. IL-17A-producing Vγ6+ γδ T cells increased in the peritoneal cavity of IL-21R KO mice more than in wild type mice after BCG infection. In contrast, the number of IL-17A-producing Vγ6+ γδ T cells was significantly lower after inoculation with rBCG-Ag85B-IL-21 compared with control rBCG-Ag85B. Notably, exogenous IL-21 selectively induced apoptosis of IL-17A-producing Vγ6+ γδ T cells via Bim. Thus, these results suggest that IL-21 acts as a potent inhibitor of a IL-17A-producing γδ T-cell subset during BCG infection.

scholarly journals Host-derived lipids orchestrate pulmonary γδ T cell response to provide early protection against influenza virus infection

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiaohui Wang ◽  
Xiang Lin ◽  
Zihan Zheng ◽  
Bingtai Lu ◽  
Jun Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Influenza Virus Infection ◽  
Γδ T Cells ◽  
T Cell Response ◽  
Host Cells ◽  
Interleukin 17 ◽  
Γδ T Cell ◽  
Innate Defense

AbstractInnate immunity is important for host defense by eliciting rapid anti-viral responses and bridging adaptive immunity. Here, we show that endogenous lipids released from virus-infected host cells activate lung γδ T cells to produce interleukin 17 A (IL-17A) for early protection against H1N1 influenza infection. During infection, the lung γδ T cell pool is constantly supplemented by thymic output, with recent emigrants infiltrating into the lung parenchyma and airway to acquire tissue-resident feature. Single-cell studies identify IL-17A-producing γδ T (Tγδ17) cells with a phenotype of TCRγδhiCD3hiAQP3hiCXCR6hi in both infected mice and patients with pneumonia. Mechanistically, host cell-released lipids during viral infection are presented by lung infiltrating CD1d+ B-1a cells to activate IL-17A production in γδ T cells via γδTCR-mediated IRF4-dependent transcription. Reduced IL-17A production in γδ T cells is detected in mice either lacking B-1a cells or with ablated CD1d in B cells. Our findings identify a local host-immune crosstalk and define important cellular and molecular mediators for early innate defense against lung viral infection.

scholarly journals Identification of leptospiral protein antigens recognized by WC1+ γδ T cell subsets as target for development of recombinant vaccines

2021 ◽  
Author(s):  
Aline Teixeira ◽  
Alexandria Gillespie ◽  
Alehegne Yirsaw ◽  
Emily Britton ◽  
Janice Telfer ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Outer Membrane Proteins ◽  
Γδ T Cells ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Economic Losses ◽  
Γδ T Cell ◽  
Protein Antigens

Pathogenic Leptospira species cause leptospirosis, a neglected zoonotic disease recognized as a global public health problem. It is also the cause of the most common cattle infection that results in major economic losses due to reproductive problems. γδ T cells play a role in the protective immune response in livestock species against Leptospira while human γδ T cells also respond to Leptospira. Thus, activation of γδ T cells has emerged as a potential component for optimization of vaccine strategies. Bovine γδ T cells proliferate and produce IFN-γ in response to vaccination with inactivated leptospires and this response is mediated by a specific subpopulation of the WC1-bearing γδ T cells. WC1 molecules are members of the group B scavenger receptor cysteine rich (SRCR) superfamily and are composed of multiple SRCR domains, of which particular extracellular domains act as ligands for Leptospira. Since WC1 molecules function as both pattern recognition receptors and γδ TCR coreceptors, the WC1 system has been proposed as a novel target to engage γδ T cells. Here, we demonstrate the involvement of leptospiral protein antigens in the activation of WC1+ γδ T cells and identified two leptospiral outer membrane proteins able to interact directly with them. Interestingly, we show that the protein-specific γδ T cell response is composed of WC1.1+ and WC1.2+ subsets, although a greater number of WC1.1+ γδ T cells respond. Identification of protein antigens will enhance our understanding of the role γδ T cells play in the leptospiral immune response and in recombinant vaccine development.

Helper activity of CD4+ αβ T cells is required for the avian γδ T cell response

1993 ◽  
Vol 23 (8) ◽  
pp. 2034-2037 ◽  
Author(s):  
T. Petteri Arstila ◽  
Paavo Toivanen ◽  
Olli Lassila
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Γδ T Cell ◽  
Helper Activity ◽  
Αβ T Cells

scholarly journals Loss of Immunization-Induced Epitope-Specific CD4 T-Cell Response following Anaplasma marginale Infection Requires Presence of the T-Cell Epitope on the Pathogen and Is Not Associated with an Increase in Lymphocytes Expressing Known Regulatory Cell Phenotypes

2015 ◽  
Vol 22 (7) ◽  
pp. 742-753 ◽  
Author(s):  
Wendy C. Brown ◽  
Joshua E. Turse ◽  
Paulraj K. Lawrence ◽  
Wendell C. Johnson ◽  
Glen A. Scoles ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Cell Epitope ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Γδ T Cell ◽  
Content Type ◽  
Cell Responses

ABSTRACTWe have shown that in cattle previously immunized with outer membrane proteins, infection withAnaplasma marginaleinduces a functionally exhausted CD4 T-cell response to theA. marginaleimmunogen. Furthermore, T-cell responses following infection in nonimmunized cattle had a delayed onset and were sporadic and transient during persistent infection. The induction of an exhausted T-cell response following infection presumably facilitates pathogen persistence. In the current study, we hypothesized that the loss of epitope-specific T-cell responses requires the presence of the immunizing epitope on the pathogen, and T-cell dysfunction correlates with the appearance of regulatory T cells. In limited studies in cattle, regulatory T cells have been shown to belong to γδ T-cell subsets rather than be CD4 T cells expressing forkhead box protein P3 (FoxP3). Cattle expressing the DRB3*1101 haplotype were immunized with a truncatedA. marginalemajor surface protein (MSP) 1a that contains a DRB3*1101-restricted CD4 T-cell epitope, F2-5B. Cattle either remained unchallenged or were challenged withA. marginalebacteria that express the epitope or withA. marginalesubsp.centralethat do not. Peripheral blood and spleen mononuclear cells were monitored for MSP1a epitope F2-5B-specfic T-cell proliferative responses and were stained for γδ T-cell subsets or CD4+CD25+FoxP3+T cells before and during infection. As hypothesized, the induction of T-cell exhaustion occurred only following infection withA. marginale, which did not correlate with an increase in either CD4+CD25+FoxP3+T cells or any γδ T-cell subset examined.

scholarly journals Direct Visualization of Antigen-specific CD8+T Cells during the Primary Immune Response to Epstein-Barr Virus In Vivo

1998 ◽  
Vol 187 (9) ◽  
pp. 1395-1402 ◽  
Author(s):  
M.F.C. Callan ◽  
L. Tan ◽  
N. Annels ◽  
G.S. Ogg ◽  
J.D.K. Wilson ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Epstein Barr Virus ◽  
T Cell Response ◽  
Primary Immune Response ◽  
Barr Virus ◽  
Epstein Barr

Primary infection with virus can stimulate a vigorous cytotoxic T cell response. The magnitude of the antigen-specific component versus the bystander component of a primary T cell response remains controversial. In this study, we have used tetrameric major histocompatibility complex–peptide complexes to directly visualize antigen-specific cluster of differentration (CD)8+ T cells during the primary immune response to Epstein-Barr virus (EBV) infection in humans. We show that massive expansion of activated, antigen-specific T cells occurs during the primary response to this virus. In one individual, T cells specific for a single EBV epitope comprised 44% of the total CD8+ T cells within peripheral blood. The majority of the antigen-specific cells had an activated/memory phenotype, with expression of human histocompatibility leukocyte antigen (HLA) DR, CD38, and CD45RO, downregulation of CD62 leukocyte (CD62L), and low levels of expression of CD45RA. After recovery from AIM, the frequency of antigen-specific T cells fell in most donors studied, although populations of antigen-specific cells continued to be easily detectable for at least 3 yr.

scholarly journals Vaccine-Induced Simian Immunodeficiency Virus-Specific CD8+T-Cell Responses Focused on a Single Nef Epitope Select for Escape Variants Shortly after Infection

2015 ◽  
Vol 89 (21) ◽  
pp. 10802-10820 ◽  
Author(s):  
Mauricio A. Martins ◽  
Damien C. Tully ◽  
Michael A. Cruz ◽  
Karen A. Power ◽  
Marlon G. Veloso de Santana ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Rhesus Macaques ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Group 1

ABSTRACTCertain major histocompatibility complex class I (MHC-I) alleles (e.g.,HLA-B*27) are enriched among human immunodeficiency virus type 1 (HIV-1)-infected individuals who suppress viremia without treatment (termed “elite controllers” [ECs]). Likewise,Mamu-B*08expression also predisposes rhesus macaques to control simian immunodeficiency virus (SIV) replication. Given the similarities between Mamu-B*08 and HLA-B*27, SIV-infectedMamu-B*08+animals provide a model to investigate HLA-B*27-mediated elite control. We have recently shown that vaccination with three immunodominant Mamu-B*08-restricted epitopes (Vif RL8, Vif RL9, and Nef RL10) increased the incidence of elite control inMamu-B*08+macaques after challenge with the pathogenic SIVmac239 clone. Furthermore, a correlate analysis revealed that CD8+T cells targeting Nef RL10 was correlated with improved outcome. Interestingly, this epitope is conserved between SIV and HIV-1 and exhibits a delayed and atypical escape pattern. These features led us to postulate that a monotypic vaccine-induced Nef RL10-specific CD8+T-cell response would facilitate the development of elite control inMamu-B*08+animals following repeated intrarectal challenges with SIVmac239. To test this, we vaccinatedMamu-B*08+animals withnefinserts in which Nef RL10 was either left intact (group 1) or disrupted by mutations (group 2). Although monkeys in both groups mounted Nef-specific cellular responses, only those in group 1 developed Nef RL10-specific CD8+T cells. These vaccine-induced effector memory CD8+T cells did not prevent infection. Escape variants emerged rapidly in the group 1 vaccinees, and ultimately, the numbers of ECs were similar in groups 1 and 2. High-frequency vaccine-induced CD8+T cells focused on a single conserved epitope and therefore did not prevent infection or increase the incidence of elite control inMamu-B*08+macaques.IMPORTANCESince elite control of chronic-phase viremia is a classic example of an effective immune response against HIV/SIV, elucidating the basis of this phenomenon may provide useful insights into how to elicit such responses by vaccination. We have previously established that vaccine-induced CD8+T-cell responses against three immunodominant epitopes can increase the incidence of elite control in SIV-infectedMamu-B*08+rhesus macaques—a model of HLA-B*27-mediated elite control. Here, we investigated whether a monotypic vaccine-induced CD8+T-cell response targeting the conserved “late-escaping” Nef RL10 epitope can increase the incidence of elite control inMamu-B*08+monkeys. Surprisingly, vaccine-induced Nef RL10-specific CD8+T cells selected for variants within days after infection and, ultimately, did not facilitate the development of elite control. Elite control is, therefore, likely to involve CD8+T-cell responses against more than one epitope. Together, these results underscore the complexity and multidimensional nature of virologic control of lentivirus infection.

scholarly journals T Cell Epitope Clustering in the Highly Immunogenic BZLF1 Antigen of Epstein-Barr Virus

2014 ◽  
Vol 89 (1) ◽  
pp. 703-712 ◽  
Author(s):  
Melissa J. Rist ◽  
Michelle A. Neller ◽  
Jacqueline M. Burrows ◽  
Scott R. Burrows
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Epstein Barr Virus ◽  
T Cell Response ◽  
T Cell Epitopes ◽  
Barr Virus ◽  
Epstein Barr ◽  
Hla Molecules

ABSTRACTPolymorphism in the human leukocyte antigen (HLA) loci ensures that the CD8+T cell response to viruses is directed against a diverse range of antigenic epitopes, thereby minimizing the impact of virus escape mutation across the population. The BZLF1 antigen of Epstein-Barr virus is an immunodominant target for CD8+T cells, but the response has been characterized only in the context of a limited number of HLA molecules due to incomplete epitope mapping. We have now greatly expanded the number of defined CD8+T cell epitopes from BZLF1, allowing the response to be evaluated in a much larger proportion of the population. Some regions of the antigen fail to be recognized by CD8+T cells, while others include clusters of overlapping epitopes presented by different HLA molecules. These highly immunogenic regions of BZLF1 include polymorphic sequences, such that up to four overlapping epitopes are impacted by a single amino acid variation common in different regions of the world. This focusing of the immune response to limited regions of the viral protein could be due to sequence similarity to human proteins creating “immune blind spots” through self-tolerance. This study significantly enhances the understanding of the immune response to BZLF1, and the precisely mapped T cell epitopes may be directly exploited in vaccine development and adoptive immunotherapy.IMPORTANCEEpstein-Barr virus (EBV) is an important human pathogen, associated with several malignancies, including nasopharyngeal carcinoma and Hodgkin lymphoma. T lymphocytes are critical for virus control, and clinical trials aimed at manipulating this arm of the immune system have demonstrated efficacy in treating these EBV-associated diseases. These trials have utilized information on the precise location of viral epitopes for T cell recognition, for either measuring or enhancing responses. In this study, we have characterized the T cell response to the highly immunogenic BZLF1 antigen of EBV by greatly expanding the number of defined T cell epitopes. An unusual clustering of epitopes was identified, highlighting a small region of BZLF1 that is targeted by the immune response of a high proportion of the world's population. This focusing of the immune response could be utilized in developing vaccines/therapies with wide coverage, or it could potentially be exploited by the virus to escape the immune response.

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