Biology subjects

Selin, L. K.

Publications and source records attributed to Selin, L. K..

3 recordsLinked to original sources

bioRxiv2022

Co-evolution of human influenza A and Epstein Barr virus-specific CD8 ex vivo memory T cell receptor BV repertoires with increasing age

CD8 memory T cells are generated during primary infection with intracellular pathogens, such as viruses. These cells play an important role in the protection of the host upon re-infection with the same pathogen. In this study, we compare CD8 memory T cell receptor (TCR) BV repertoires directly ex vivo for two common human viruses, influenza A virus (IAV), an RNA virus that frequently re-infects due to a high rate of genetic mutation, and Epstein-Barr virus (EBV), a DNA virus, which persists in B cells for life, in the 95% of people that become infected. In cross- sectional and longitudinal studies of EBV seropositive, HLA-A2+, young (18-22 years), middle age (25-59 years), and older (>60 years) donors, we demonstrate that CD8 memory TCR repertoires to three immunodominant epitopes, known to have cross-reactive responses, IAV- M158-66 (M1), EBV-BMLF1280-288 (BM), and EBV-BRLF109-117 (BR) co-evolve as individuals age. Cross-sectional studies showed that IAV-M1- and both EBV-specific repertoires narrowed their TRBV usage with increasing age manifesting to different degrees for each epitope. In fact, narrowing of EBV-BM and EBV-BR-specific TRBV usage correlated with increasing age. IAV- M1-specific TRBV usage was significantly narrowed by middle-age. There was evidence that TRBV usage was changing with increasing age. For instance, IAV-M1-specific dominant BV19 usage appeared to become bimodal showing either high or low frequency of usage in the older age group, while BV30 usage frequency directly correlated with age. For the EBV epitope-specific responses there was preferential usage of particular TRBV and changes in the hierarchy of BV family usage in the different age groups. There appeared to be focusing of the TRBV repertoire by all 3 epitopes to three common BV in the older donors, which would be consistent with retention of crossreactive TCR suggesting co-evolution. Longitudinal studies tracking two donors over 14- 15 years (middle age to older) showed that there were continuous modulations in the TCR repertoire of IAV-M1, EBV-BM and EBV-BR-specific responses over time. There was evidence that acute IAV infection could contribute to these changes in TCR repertoire. This could be occurring by the TCR cross-reactivity that is known to exist between these 3 epitopes, and which appeared to be enhanced during acute IAV infection based on increased usage of common shared TRBV. These studies suggest that virus-specific TCR repertoires change over time as individuals age leading to narrowing of the repertoire favoring retention of potentially crossreactive TCR.

immunology↗

bioRxiv2020

Epstein Barr virus epitope/MHC interaction combined with convergent recombination drive selection of diverse T cell receptor a and b repertoires

Recognition modes of individual T cell receptors (TCR) are well studied, but factors driving the selection of TCR repertoires from primary through persistent human virus infections are less well understood. Using deep sequencing, we demonstrate a high degree of diversity of EBV-specific clonotypes in acute infectious mononucleosis. Only 9% of unique clonotypes detected in AIM persisted into convalescence; the majority (91%) of unique clonotypes detected in AIM were not detected in convalescence and were seeming replaced by equally diverse "de-novo" clonotypes. The persistent clonotypes had a greater probability of being generated than non-persistent due to convergence recombination of multiple nucleotide sequences to encode the same amino acid sequence, as well as the use of shorter CDR3 regions with fewer nucleotide additions (i.e. sequences closer to germline). Moreover, the two most immunodominant HLA-A2-restricted EBV epitopes, BRLF1109 and BMLF1280, show highly distinct antigen-specific public (i.e. shared between individuals) features. In fact, TCR CDR3 motifs played a dominant role, while TCR{beta} played a minimal role, in the selection of TCR repertoire to an immunodominant EBV epitope, BRLF1. This contrasts with the majority of previously reported repertoires, which appear to be selected either on TCR{beta} CDR3 interactions with peptide/MHC or in combination with TCR CDR3. Understanding of how TCR/peptide/MHC complex interactions drive repertoire selection can be used to develop optimal strategies for vaccine design or generation of appropriate adoptive immunotherapies for viral infections in transplant settings or for cancer. ImportanceSeveral lines of evidence suggest that TCR and {beta} repertoires play a role in disease outcomes and treatment strategies during viral infections in transplant patients, and in cancer and autoimmune disease therapy. Our data suggests that it is essential that we understand the basic principles of how to drive optimum repertoires for both TCR chains, and {beta}. We address this important issue by characterizing the CD8 TCR repertoire to a common persistent human viral infection (EBV), which is controlled by appropriate CD8 T cell responses. The ultimate goal would be to determine if the individuals who are infected asymptomatically develop a different TCR repertoire than those that develop the immunopathology of AIM. Here, we begin by doing an in depth characterization of both CD8 T cell TCR and {beta} repertoires to two immunodominant EBV epitopes over the course of AIM identifying potential factors that may be driving their selection.

immunology↗

bioRxiv2018

High diversity, turnover, and structural constraints characterize TCR α and β repertoire selection

Recognition modes of individual T-cell receptors (TCR) are well studied, but how TCR repertoires are selected during acute through persistent human virus infections is less clear. Here, we show that persistent EBV-specific clonotypes account for only 9% of unique clonotypes but are highly expanded in acute infectious mononucleosis, and have distinct antigen-specific public features that drive selection into convalescence. The other 91% of highly diverse unique clonotypes disappear and are replaced in convalescence by equally diverse \"de-novo\" clonotypes. These broad fluctuating repertoires lend plasticity to antigen recognition and potentially protect against T-cell clonal loss and viral escape.

immunology↗