Using an IFNγ-YFP reporter system, Abdelbary et al. showed that epicutaneous VacV infection induced some skin-infiltrating effector CD8+ T cells (TEFF), but not circulating memory T cell precursors to express IFNγ in the presence of antigen. Levels of IFNγ and induction of tissue-resident CD8+ T cell (TRM) differentiation depended on TCR signal strength and expression of the transcriptional repressor Blimp1. Blimp1 was upregulated in TEFF re-exposed to antigen in the periphery, and regulated chemotaxis. Low-affinity TCR agonism bolstered CXCR6-mediated tissue retention, but strong agonism also hindered the complementary pathway of S1P-mediated TEFF egress.
Contributed by Paula Hochman
ABSTRACT: Tissue-resident memory (TRM) CD8+ T cells are largely derived from recently activated effector T cells, but the mechanisms that control the extent of TRM differentiation within tissue microenvironments remain unresolved. Here, using an IFNγ-YFP reporter system to identify CD8+ T cells executing antigen-dependent effector functions, we define the transcriptional consequences and functional mechanisms controlled by TCR-signaling strength that occur within the skin during viral infection to promote TRM differentiation. TCR-signaling both enhances CXCR6-mediated migration and suppresses migration toward sphingosine-1-phosphate, indicating the programming of a 'chemotactic switch' following secondary antigen encounter within non-lymphoid tissues. Blimp1 was identified as the critical target of TCR re-stimulation that is necessary to establish this chemotactic switch and for TRM differentiation to efficiently occur. Collectively, our findings show that access to antigen presentation and strength of TCR-signaling required for Blimp1 expression establishes the chemotactic properties of effector CD8+ T cells to promote residency within non-lymphoid tissues.
