Inhibitory IL-10-producing CD4+ T cells are T-bet-dependent and facilitate cytomegalovirus persistence via coexpression of arginase-1.

Inhibitory CD4+ T cells have been linked with suboptimal immune responses against cancer and pathogen chronicity. However, the mechanisms that underpin the development of these regulatory cells, especially in the context of ongoing antigen exposure, have remained obscure. To address this knowledge gap, we undertook a comprehensive functional, phenotypic, and transcriptomic analysis of interleukin (IL)-10-producing CD4+ T cells induced by chronic infection with murine cytomegalovirus (MCMV). We identified these cells as clonally expanded and highly differentiated TH1-like cells that developed in a T-bet-dependent manner and coexpressed arginase-1 (Arg1), which promotes the catalytic breakdown of L-arginine. Mice lacking Arg1-expressing CD4+ T cells exhibited more robust antiviral immunity and were better able to control MCMV. Conditional deletion of T-bet in the CD4+ lineage suppressed the development of these inhibitory cells and also enhanced immune control of MCMV. Collectively, these data elucidated the ontogeny of IL-10-producing CD4+ T cells and revealed a previously unappreciated mechanism of immune regulation, whereby viral persistence was facilitated by the site-specific delivery of Arg1.

Unique features of the TCR repertoire of reactivated memory T cells in the experimental mouse tumor model.

T cell engineering with T cell receptors (TCR) specific to tumor antigens has become a breakthrough towards personalized cancer adoptive cell immunotherapy. However, the search for therapeutic TCRs is often challenging, and effective strategies are strongly required for the identification and enrichment of tumor-specific T cells that express TCRs with superior functional characteristics. Using an experimental mouse tumor model, we studied sequential changes in TCR repertoire features of T cells involved in the primary and secondary immune responses to allogeneic tumor antigens. In-depth bioinformatics analysis of TCR repertoires showed differences in reactivated memory T cells compared to primarily activated effectors. After cognate antigen re-encounter, memory cells were enriched with clonotypes that express α-chain TCR with high potential cross-reactivity and enhanced strength of interaction with both MHC and docked peptides. Our findings suggest that functionally true memory T cells could be a better source of therapeutic TCRs for adoptive cell therapy. No marked changes were observed in the physicochemical characteristics of TCRß in reactivated memory clonotypes, indicative of the dominant role of TCRα in the secondary allogeneic immune response. The results of this study could further contribute to the development of TCR-modified T cell products based on the phenomenon of TCR chain centricity.

Naïve Regulatory T Cell Subset Is Altered in X-Linked Agammaglobulinemia.

The interplay between T- and B-cell compartments during naïve, effector and memory T cell maturation is critical for a balanced immune response. Primary B-cell immunodeficiency arising from X-linked agammaglobulinemia (XLA) offers a model to explore B cell impact on T cell subsets, starting from the thymic selection. Here we investigated characteristics of naïve and effector T cell subsets in XLA patients, revealing prominent alterations in the corresponding T-cell receptor (TCR) repertoires. We observed immunosenescence in terms of decreased diversity of naïve CD4+ and CD8+ TCR repertoires in XLA donors. The most substantial alterations were found within naïve CD4+ subsets, and we have investigated these in greater detail. In particular, increased clonality and convergence, along with shorter CDR3 regions, suggested narrower focused antigen-specific maturation of thymus-derived naïve Treg (CD4+CD45RA+CD27+CD25+) in the absence of B cells - normally presenting diverse self and commensal antigens. The naïve Treg proportion among naïve CD4 T cells was decreased in XLA patients, supporting the concept of impaired thymic naïve Treg selection. Furthermore, the naïve Treg subset showed prominent differences at the transcriptome level, including increased expression of genes specific for antigen-presenting and myeloid cells. Altogether, our findings suggest active B cell involvement in CD4 T cell subsets maturation, including B cell-dependent expansion of the naïve Treg TCR repertoire that enables better control of self-reactive T cells.