Narrowing of Human Influenza A Virus-Specific T Cell Receptor α and β Repertoires with Increasing Age

Abstract

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 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. IMPORTANCEWith increasing age, the immune system undergoes drastic changes, and older individuals have declined resistance to infections. Vaccinations become less effective, and infection with influenza A virus in older individuals is associated with higher morbidity and mortality. Here, we questioned whether T cell responses directed against the highly conserved HLA-A2-restricted M1 58 -66 peptide of IAV evolves with increasing age. Specifically, we postulated that CD8 T cell repertoires narrow with recurrent exposure and may thus be less efficient in response to new infections with new strains of IAV. Detailed analyses of the VA and VB TCR repertoires simultaneously showed a direct correlation between increasing age and narrowing of the TCR repertoire. Features of the TCRs indicated potentially enhanced cross-reactivity in all older donors. In summary, T cell repertoire analysis in older individuals may be useful as one of the predictors of protection after vaccination. Remarkable progress in medicine combined with public health policy and socioeconomic development has resulted in longer life spans than ever before. It was predicted that in 2050 the proportion of people aged 65 years and older in the United States will more than double to 22% from the 10% in the year 2000 (1). This will present challenges and will have an impact on health care systems, and reversing the negative effects of aging would profit individuals and society. An age-related phenomenon known as "immunosenescence," where both innate and adaptive immune responses become impaired, can result in deleterious clinical endpoints (2). This process is linked to declining resistance to infections and the poor efficacy of vaccines in older individuals (3).Earlier reports have shown that T cell receptor (TCR) repertoire diversity is a key component of protection from infection (4-7). TCR gene sequences present unique markers for tracking T cell diversity. During agi...

Diversification of the antigen-specific T cell receptor repertoire after varicella zoster vaccination

“…Moreover, contraction was caused by a preferential loss of infrequent T cell clones, consistent with the interpretation of greater selection of dominant T cell specificities. A similar observation of contraction at the epitope level has been made for the repertoire of influenza-specific CD8 T cells in older individuals suggesting that age may be a contributing factor (20). The clinical relevance of repertoire diversity has been shown for CMV infection, where the number of different TCRs reactive to a CMV peptide was more important for effective control of viral latency than their frequencies (17).…”

“…In general, during infection or vaccination, epitope-specific naive CD8 T cells are recruited into the memory compartment. However, deterministic selection mechanisms cause skewed clonal size distributions that further increase in chronic infections and recall responses (19, 20). These observations raise the question of whether vaccination induces a contraction of the virus specific repertoire owing to the disproportionate expansion of dominant clones.…”

Broad TCR repertoire and diverse structural solutions for recognition of an immunodominant CD8+ T cell epitope

“…These numbers are in line with estimates of the precursor frequency of naïve T cells recognizing various antigenic peptides in other mouse and human models 38–40 . Overall diversity measures for this repertoire were at the upper end of the range of values previously reported for other viral epitope-specific responses 19,32,41,42 . As previously reported, a single public TRBV gene segment (TRBV19) with restricted CDR3β motif (xRS/Ax) (Group I) dominated the HLA-A2/M1 response, representing in this cohort ~50% (range 15–72%) of the responding CD8 T cells and 12–55% of the unique sequences.…”

“…We then used HLA-A2/M1 dextramer to sort antigen-specific cells before isolating cDNA for NGS analysis of the TRAV and TRBV repertoires. Previous approaches using 5’-RACE PCR 12 , or using individual primers for each TRAV or TRBV gene and then subcloning 32 , were not designed to exhaustively sample the repertoire, and on average identified 20–100 unique TCRα or TCRβ clonotypes specific to HLA-A2/M1 in any donor, usually examining either TRAV or TRBV repertoire but not both 11,12,32 . Using the ex vivo expansion/NGS strategy we gained a greater appreciation of the complete M1-specific TCR repertoire.…”

CD8+ T cells specific for the islet autoantigen IGRP are restricted in their T cell receptor chain usage

“…S1a). From the analysed cells, we identified new as well as previously described22232930 Flu MP 58-66 -specific T cell receptor chains (see Supplementary Table S1). We noted inter-individual sharing of TCR α-chains among the analysed Flu-specific cells (Supplementary Fig.…”