Human γδ T‐cell receptor repertoire is shaped by influenza viruses, age and tissue compartmentalisation (original) (raw)
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Frontiers in immunology, 2018
CD8 T cells recognizing antigenic peptides derived from conserved internal viral proteins confer broad protection against distinct influenza viruses. As memory CD8 T cells change throughout the human lifetime and across tissue compartments, we investigated how T cell receptor (TCR) composition and diversity relate to memory CD8 T cells across anatomical sites and immunological phases of human life. We used peptide-HLA tetramer magnetic enrichment, single-cell multiplex RT-PCR for both the TCR-alpha (TCRα) and TCR-beta (TCRβ) chains, and new TCRdist and grouping of lymphocyte interactions by paratope hotspots (GLIPH) algorithms to compare TCRs directed against the most prominent human influenza epitope, HLA-A*02:01-M1 (A2M1). We dissected memory TCR repertoires directed toward A2M1 CD8 T cells within human tissues and compared them to human peripheral blood of young and elderly adults. Furthermore, we compared these memory CD8 T cell repertoires to A2M1 CD8 TCRs during acute influenz...
Narrowing of human influenza A virus specific T cell receptor α and β repertoire with increasing age
Journal of Virology, 2015
We questioned whether memory CD8 responses to this nonpersistent virus, to which recurrent exposure with new strains is common, changed over time with increasing age. Here, we show a direct correlation between increasing age and narrowing of the HLA-A2-restricted IAV V␣ and V T cell repertoires specific to M1 residues 58 to 66 (M1 58 -66 ), which simultaneously lead to oligoclonal expansions, including the usage of a single identical VA12-JA29 clonotype in all eight older donors. The V␣ repertoire of older individuals also had longer CDR3 regions with increased usage of G/A runs, whose molecular flexibility may enhance T cell receptor (TCR) promiscuity. Collectively, these results suggest that CD8 memory T cell responses to nonpersistent viruses like IAV in humans are dynamic, and with aging there is a reduced diversity but a preferential retention of T cell repertoires with features of enhanced crossreactivity.
Influenza A antigen exposure selects dominant V_β17^+ TCR in human CD8^+ cytotoxic T cell responses
International Immunology, 2001
are generated which aid virus clearance. We have observed that in HLA-A*0201 ⍣ subjects, CTL expressing V β 17 ⍣ TCR and recognizing a peptide from the influenza A matrix protein (M1 58-66 ) dominate this response. In experimental models of infection such dominance can be due to inheritance of a restricted T cell repertoire or acquired consequent on expansion of CTL bearing an optimum TCR conformation against the MHC-peptide complex. To examine how influenza A infection might influence the development of TCR V β 17 expansion, we studied influenza A-specific CTL in a cross-sectional study of 82 HLA-A*0201 ⍣ individuals from birth (cord blood) to adulthood. Primary M1 58-66 -specific CTL were detected in cord blood, but their TCR were diverse and depletion of V β 17 ⍣ cells did not abrogate specific cytotoxicity. In contrast following natural influenza A infection, TCR V β 17 ⍣ CTL dominated to the extent that only one of nine adult CTL lines retained any functional activity after in vitro depletion of V β 17 ⍣ CTL. These results suggest that the dominance of V β 17 ⍣ TCR among adult M1 58-66 -specific CTL results from maturation and focussing of the response driven by exposure to influenza, and have implications for optimum immunization strategies.
Journal of Virology, 2015
Alterations in memory CD8 T cell responses may contribute to the high morbidity and mortality caused by seasonal influenza A virus (IAV) infections in older individuals. We questioned whether memory CD8 responses to this nonpersistent virus, to which recurrent exposure with new strains is common, changed over time with increasing age. Here, we show a direct correlation between increasing age and narrowing of the HLA-A2-restricted IAV Vα and Vβ T cell repertoires specific to M1 residues 58 to 66 (M1 58–66 ), which simultaneously lead to oligoclonal expansions, including the usage of a single identical VA12-JA29 clonotype in all eight older donors. The Vα repertoire of older individuals also had longer CDR3 regions with increased usage of G/A runs, whose molecular flexibility may enhance T cell receptor (TCR) promiscuity. Collectively, these results suggest that CD8 memory T cell responses to nonpersistent viruses like IAV in humans are dynamic, and with aging there is a reduced diver...
Perturbed CD8 + T cell immunity across universal influenza epitopes in the elderly
Journal of Leukocyte Biology
Influenza epidemics lead to severe illness, life-threatening complications and deaths, especially in the elderly. As CD8 + T-cells are associated with rapid recovery from influenza, we investigated the effects of aging on antigen-specific CD8 + T-cells across the universal influenza epitopes in humans. We show that aging is characterised by altered frequencies in T-cell subsets, with naïve T-cells being partially replaced by activated effector/memory populations. Although we observed no striking differences in T-cell receptor (TCR) signalling capacity, T-cells in the elderly had increased expression of transcription factors Eomes and T-bet, and such changes were most apparent in CD8 + T-cells. Strikingly, the numbers of antigen-specific CD8 + T-cells across universal influenza epitopes were reduced in the elderly, although their effector/memory phenotypes remained stable. To understand whether diminished numbers of influenza-specific CD8 + T-cells in the elderly resulted from alteration in TCR clonotypes, we dissected TCRab repertoire specific for the prominent HLA-A*02:01-restricted-M1 58-66 (A2/M1 58) influenza epitope. We provide the first ex vivo data on paired antigen-specific TCRab clonotypes in the elderly, showing that influenzaspecific A2/M1 58 + TCRab repertoires in the elderly adults varied from those in younger adults, with the main features being a reduction in the frequency of the public TRAV27-TRBV19 TCRab clonotype, increased proportion of private TCRab signatures, broader usage of TRAV and TRBV gene segments, and large clonal expansion of private TCRab clonotypes with longer CDR3 loops. Our study supports the development of T-cell-targeted influenza vaccines that would boost the T-cell compartment during life, and maintain the numbers and optimal TCRab signatures in the elderly.
Influenza A antigen exposure selects dominant Vbeta17+ TCR in human CD8+ cytotoxic T cell responses
International Immunology, 2001
are generated which aid virus clearance. We have observed that in HLA-A*0201 ⍣ subjects, CTL expressing V β 17 ⍣ TCR and recognizing a peptide from the influenza A matrix protein (M1 58-66 ) dominate this response. In experimental models of infection such dominance can be due to inheritance of a restricted T cell repertoire or acquired consequent on expansion of CTL bearing an optimum TCR conformation against the MHC-peptide complex. To examine how influenza A infection might influence the development of TCR V β 17 expansion, we studied influenza A-specific CTL in a cross-sectional study of 82 HLA-A*0201 ⍣ individuals from birth (cord blood) to adulthood. Primary M1 58-66 -specific CTL were detected in cord blood, but their TCR were diverse and depletion of V β 17 ⍣ cells did not abrogate specific cytotoxicity. In contrast following natural influenza A infection, TCR V β 17 ⍣ CTL dominated to the extent that only one of nine adult CTL lines retained any functional activity after in vitro depletion of V β 17 ⍣ CTL. These results suggest that the dominance of V β 17 ⍣ TCR among adult M1 58-66 -specific CTL results from maturation and focussing of the response driven by exposure to influenza, and have implications for optimum immunization strategies.
Journal of Virology, 2016
Novel influenza viruses often cause differential infection patterns across different age groups, an effect that is defined as heterogeneous demographic susceptibility. This occurred during the A/H2N2 pandemic, when children experienced higher influenza attack rates than adults. Since the recognition of conserved epitopes across influenza subtypes by CD8 ؉ cytotoxic T lymphocytes (CTLs) limit influenza disease, we hypothesized that conservation of CTL antigenic peptides (Ag-p) in viruses circulating before the pH2N2-1957 may have resulted in differential CTL immunity. We compared viruses isolated in the years preceding the pandemic (1941 to 1957) to which children and adults were exposed to viruses circulating decades earlier (1918 to 1940), which could infect adults only. Consistent with phylogenetic models, influenza viruses circulating from 1941 to 1957, which infected children, shared with pH2N2 the majority (ϳ89%) of the CTL peptides within the most immunogenic nucleoprotein, matrix 1, and polymerase basic 1, thus providing evidence for minimal pH2N2 CTL escape in children. Our study, however, identified potential CTL immune evasion from pH2N2 irrespective of age, within HLA-A*03:01 ؉ individuals for PB1 471-L473V/N476I variants and HLA-B*15:01 ؉ population for NP 404-414-V408I mutant. Further experiments using the murine model of B-cell-deficient mice showed that multiple influenza infections resulted in superior protection from influenza-induced morbidity, coinciding with accumulation of tissue-resident memory CD8 ؉ T cells in the lung. Our study suggests that protection against H2N2-1957 pandemic influenza was most likely linked to the number of influenza virus infections prior to the pandemic challenge rather than differential preexisting CTL immunity. Thus, the regimen of a CTL-based vaccine/vaccine-component may benefit from periodic boosting to achieve fully protective, asymptomatic influenza infection. IMPORTANCE Due to a lack of cross-reactive neutralizing antibodies, children are particularly susceptible to influenza infections caused by novel viral strains. Preexisting T cell immunity directed at conserved viral regions, however, can provide protection against influenza viruses, promote rapid recovery and better clinical outcomes. When we asked whether high susceptibility of children (compared to adults) to the pandemic H2N2 influenza strain was associated with immune evasion from T-cell immunity, we found high conservation within T-cell antigenic regions in pandemic H2N2. However, the number of influenza infections prior to the challenge was linked to protective, asymptomatic infections and establishment of tissue-resident memory T cells. Our study supports development of vaccines that prime and boost T cells to elicit cross-strain protective T cells, especially tissueresident memory T cells, for lifelong immunity against distinct influenza viruses.