Antigen recognition by CD8+ T cells in non-lymphoid tissues initiates a transcriptional program of tissue-resident memory differentiation

Abstract

Abstract Tissue-resident memory (TRM) CD8+ T cells permanently reside in non-lymphoid tissues where they are important mediators of both host defense and inflammatory disease. TRM cells are derived from effector cells after they have entered non-lymphoid tissues, but the mechanisms that control TRM differentiation are largely undefined. We have recently used a model of localized epicutaneous infection with Vaccinia viruses (VacV) expressing unique model antigens to demonstrate that antigen recognition in the skin microenvironment enhances TRM formation by ~50–100 fold. To understand how T cell receptor (TCR) engagement may promote TRM differentiation, we sought to identify CD8+ T cells that were actively recognizing cognate peptide-MHC in vivo. Using an endogenous interferon-gamma (IFNγ)-YFP reporter, we found that only ~20% of the antigen-specific CD8+ T cells in the skin microenvironment produce IFNγ during a VacV skin infection. However, genome-wide transcriptional profiling revealed that the T cells producing IFNγ in the skin were also undergoing changes in gene expression that resemble mature TRM cells. In fact, IFNγ+ CD8+ T cells also expressed the transcription factor Blimp1, which has been shown to be critical for the acquisition of the core TRM transcriptional profile. TCR stimulation induced Blimp1 expression in effector, but not naïve, CD8+ T cells, suggesting that a secondary antigen encounter promotes unique transcriptional programming when recently activated CD8+ T cells exhibit their effector functions. Thus, antigen recognition by effector CD8+ T cells in non-lymphoid tissues is a critical factor impacting gene expression, which ultimately promotes the differentiation of TRM cells during viral skin infection.