Broad Cross-Reactive TCR Repertoires Recognizing Dissimilar Epstein-Barr and Influenza A Virus Epitopes

Clute, Shalyn Catherine; Naumov, Yuri N.; Watkin, Levi B.; Aslan, Nuray; Sullivan, John L.; Thorley‐Lawson, David A.; Luzuriaga, Katherine; Welsh, Raymond M.; Puzone, Roberto; Celada, Franco; Selin, Liisa K.

doi:10.4049/jimmunol.1000812

Cited by 58 publications

(88 citation statements)

References 49 publications

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“…Several studies have shown the existence of such heterologous immunity for a variety of viruses, including EBV (53,54). This phenomenon mostly resulted in a skewing of the epitope-specific TCRb repertoire, although a recent study posed the possibility of a diverse heterologous repertoire (55). Finally, disparate nonrestricting MHC alleles have been shown to alter the available repertoire of cognate clonotypes through selective thymic deletion (56).…”

Section: Discussionmentioning

confidence: 99%

CD8+ TCR Repertoire Formation Is Guided Primarily by the Peptide Component of the Antigenic Complex

Koning

Costa

Hoof

et al. 2013

The Journal of Immunology

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CD8+ T cells recognize infected or dysregulated cells via the clonotypically expressed αβ TCR, which engages Ag in the form of peptide bound to MHC class I (MHC I) on the target cell surface. Previous studies have indicated that a diverse Ag-specific TCR repertoire can be beneficial to the host, yet the determinants of clonotypic diversity are poorly defined. To better understand the factors that govern TCR repertoire formation, we conducted a comprehensive clonotypic analysis of CD8+ T cell populations directed against epitopes derived from EBV and CMV. Neither pathogen source nor the restricting MHC I molecule were linked with TCR diversity; indeed, both HLA-A and HLA-B molecules were observed to interact with an overlapping repertoire of expressed TRBV genes. Peptide specificity, however, markedly impacted TCR diversity. In addition, distinct peptides sharing HLA restriction and viral origin mobilized TCR repertoires with distinct patterns of TRBV gene usage. Notably, no relationship was observed between immunodominance and TCR diversity. These findings provide new insights into the forces that shape the Ag-specific TCR repertoire in vivo and highlight a determinative role for the peptide component of the peptide–MHC I complex on the molecular frontline of CD8+ T cell–mediated immune surveillance.

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Section: Discussionmentioning

confidence: 99%

CD8+ TCR Repertoire Formation Is Guided Primarily by the Peptide Component of the Antigenic Complex

Koning

Costa

Hoof

et al. 2013

The Journal of Immunology

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“…There are also preferential expansions of cross-reactive populations of CD8 T cells which can alter the hierarchy of antigen-specific T cell responses, as in lymphocytic choriomeningitis virus-immune mice infected with Pichinde virus, where a subdominant response to the nucleoprotein epitope NP 205-212 becomes dominant (50). In humans it is already wellknown that the IAV M1 58 -66 epitope is highly cross-reactive with other immunodominant HLA-A2-presented epitopes: the EBV BMFL1 epitope from residues 280 to 288 (BMLF1 280 -288 ) and the HIV p17 Gag epitope from residues 77 to 85 (24,40,51). It was previously shown that a substantial part of the acute EBV BMLF1 280 -288 -specific CD8 T cell response during acute infectious mononucleosis (AIM) is mediated by T cells cross-reactive with IAV M1 58 -66 (24).…”

Section: Discussionmentioning

confidence: 99%

“…Due to the highly conserved nature of the M1 protein, clonal senescence may play a role. It is possible that the commonly used VA27-JA42 clonotypes in middle-aged donors may undergo clonal exhaustion or clonal senescence as a result of repeated stimulation of the CD8 T cell response resulting from recurrent seasonal IAV infections or various cross-reactive exposures between different individuals (24,40). On the basis of mouse studies, in some cases the decline in the diversity of the naive TCR repertoire was so extreme that this resulted in holes in the repertoire against usually immunodominant epitopes in aged mice (29).…”

Section: Discussionmentioning

confidence: 99%

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

Gil

Yassai

Naumov

et al. 2015

J Virol

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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...

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“…31 However, during a human study with less similar crossreactive epitopes, Epstein-Barr virus (EBV)-BMLF1 280 and IAV-M1 58 , presumably lower affinity, led to broadening of the crossreactive TCR repertoire during infectious mononucleosis. 59 In general, in vivo studies in mice have shown that an infection with an unrelated virus will induce the formation of new memory cells specific to the second virus and will delete memory cells specific to the previously encountered virus. 35,60 This is a permanent change that remains for the lifetime of the mouse, unless viral antigens remain present or are re-introduced, though this has never been sufficiently studied in humans.…”

Section: Heterologous Immunity and T Cell Crossreactivitymentioning

confidence: 99%

“…[57][58][59][60] In a T cell repertoire, that which is common between individuals, be it TCR VA usage or a common amino acid sequence or 'motif', is a public specificity; that which is different between individuals, such as a CDR3 sequence, is a 'private' specificity. Thus, genetically identical hosts have, as a consequence of random DNA recombination events, genetically different immune systems, and this diversity of TCR usage poses a challenge when one considers whether an epitope-specific T cell response may be crossreactive with another epitope.…”

Section: Heterologous Immunity and T Cell Crossreactivitymentioning

confidence: 99%

Vaccination and heterologous immunity: educating the immune system

Gil¹,

Kenney²,

Mishra³

et al. 2015

Transactions of the Royal Society of Tropical Medicine and Hygiene

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This review discusses three inter-related topics: (1) the immaturity of the neonatal and infant immune response; (2) heterologous immunity, where prior infection history with unrelated pathogens alters disease outcome resulting in either enhanced protective immunity or increased immunopathology to new infections, and (3) epidemiological human vaccine studies that demonstrate vaccines can have beneficial or detrimental effects on subsequent unrelated infections. The results from the epidemiological and heterologous immunity studies suggest that the immune system has tremendous plasticity and that each new infection or vaccine that an individual is exposed to during a lifetime will potentially alter the dynamics of their immune system. It also suggests that each new infection or vaccine that an infant receives is not only perturbing the immune system but is educating the immune system and laying down the foundation for all subsequent responses. This leads to the question, is there an optimum way to educate the immune system? Should this be taken into consideration in our vaccination protocols?

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Broad Cross-Reactive TCR Repertoires Recognizing Dissimilar Epstein-Barr and Influenza A Virus Epitopes

Cited by 58 publications

References 49 publications

CD8+ TCR Repertoire Formation Is Guided Primarily by the Peptide Component of the Antigenic Complex

CD8+ TCR Repertoire Formation Is Guided Primarily by the Peptide Component of the Antigenic Complex

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

Vaccination and heterologous immunity: educating the immune system

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