Abstract
CD8 T cells play a crucial role in providing protection from viral infections. It has recently been established that a subset of CD8 T cells expressing Tcf1 are responsible for sustaining exhausted T cells during chronic lymphocytic choriomeningitis virus (LCMV) infection. Many of these studies, however, have been performed using T cell receptor (TCR) transgenic mice, in which CD8 T cells express a monoclonal TCR specific for the LCMV glycoprotein. To investigate whether the Tcf1+ and Tcf1- repertoires are naturally composed of similar or different clones in wild-type mice exposed to acute or chronic LCMV infection, we performed TCR repertoire sequencing of virus-specific CD8 T cells, including Tcf1+ and Tcf1- populations. Our analysis revealed that the Tcf1+ TCR repertoire is maintained at an equal or higher degree of clonal diversity despite harboring fewer cells. Additionally, within the same animal, there was extensive clonal overlap between the Tcf1+ and Tcf1- repertoires in both chronic and acute LCMV infection. We could further detect these virus-specific clones in longitudinal blood samples earlier in the infection. With respect to common repertoire parameters (clonal overlap, germline gene usage, and clonal expansion), we found minor differences between the virus-specific TCR repertoire of acute and chronic LCMV infection 40 days post infection. Overall, our results indicate that the Tcf1+ population emerging during chronic LCMV infection is not clonally distinct from the Tcf1- population, supporting the notion that the Tcf1+ pool is indeed a fuel for the more exhausted Tcf1– population within the heterogenous repertoire of LCMV-specific CD8 T cells.
Highlights
Viral infections represent a global health problem and often invoke a potent immune response that can potentially result in severe immunopathology to the host if not counter-balanced by immunomodulatory circuits [1, 2]
We performed longitudinal sequencing on the T cell receptor (TCR) variable beta chain (TRB) repertoire in nine mice with acute or chronic lymphocytic choriomeningitis virus (LCMV) infection; mice were of the transgenic T cell factor 1 (Tcf1) reporter strain [Tcf7GFP, which expresses GFP under the control of the Tcf7 promoter that encodes Tcf1 [8]] (Figure 1A)
Those PD-1hi CD8 T cells lacking specificity toward the gp33−41 epitope (GP33-) were sorted from mice with chronic LCMV infection to include cells with other LCMV-specificities. While this sorting strategy resulted in a discrepancy between infection cohorts for those T cell populations unspecific to gp33−41, it allowed the comparison between Tcf1+ and Tcf1– repertoires across repertoires skewed toward LCMVspecificity
Summary
Viral infections represent a global health problem and often invoke a potent immune response that can potentially result in severe immunopathology to the host if not counter-balanced by immunomodulatory circuits [1, 2]. Replicating chronic viral infections are characterized by a continuous high-level of viral antigen, which leads to excessive activation of virus-specific CD8 T cells This potent and prolonged activation typically results in T cell. Virus-Specific Tcf Repertoires exhaustion, where the upregulation of many inhibitory molecules concurs with a decrease in effector functions [2, 3]. This phenomenon has been extensively researched in the LCMV murine infection model, in which both CD8 T cell-dependent clearance of acute (resolved within 2 weeks) and humoral mediated control of chronic (resolved after months) infection can be induced, depending on the dose and strain of the inoculating virus [4]. The adaptive host immune system emphasizes on the humoral response, characterized by pronounced differentiation [5, 6] and sustained activity of T follicular helper cells, which are crucial for the eventual development of infection-resolving LCMVneutralizing antibodies [7]
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