Developmental plasticity allows outside-in immune responses by resident memory T cells.

Central memory T (TCM) cells patrol lymph nodes and perform conventional memory responses on restimulation: proliferation, migration and differentiation into diverse T cell subsets while also self-renewing. Resident memory T (TRM) cells are parked within single organs, share properties with terminal effectors and contribute to rapid host protection. We observed that reactivated TRM cells rejoined the circulating pool. Epigenetic analyses revealed that TRM cells align closely with conventional memory T cell populations, bearing little resemblance to recently activated effectors. Fully differentiated TRM cells isolated from small intestine epithelium exhibited the potential to differentiate into TCM cells, effector memory T cells and TRM cells on recall. Ex-TRM cells, former intestinal TRM cells that rejoined the circulating pool, heritably maintained a predilection for homing back to their tissue of origin on subsequent reactivation and a heightened capacity to redifferentiate into TRM cells. Thus, TRM cells can rejoin the circulation but are advantaged to re-form local TRM when called on.

IFN-ß Selectively Inhibits IL-2 Production through CREM-Mediated Chromatin Remodeling.

IFN-ß is widely used in the treatment of multiple sclerosis, yet the mechanism facilitating its efficacy remains unclear. IL-2 production by activated T cells, including those mediating autoimmunity, and subsequent autocrine stimulation is vital for T cell expansion and function. In this study, we demonstrate that in mouse and human T cells, IFN-ß specifically inhibits the production of IL-2 upon TCR engagement without affecting other cytokines or activation markers. Rather than disrupting TCR signaling, IFN-ß alters histone modifications in the IL-2 promoter to retain the locus in an inaccessible configuration. This in turn is mediated through the upregulation of the transcriptional suppressor CREM by IFN-ß and consequent recruitment of histone deacetylases to the IL-2 promoter. In accordance, ablation of CREM expression or inhibition of histone deacetylases activity eliminates the suppressive effects of IFN-ß on IL-2 production. Collectively, these findings provide a molecular basis by which IFN-ß limits T cell responses.

CD4+ resident memory T cells dominate immunosurveillance and orchestrate local recall responses.

This study examines the extent to which memory CD4+ T cells share immunosurveillance strategies with CD8+ resident memory T cells (TRM). After acute viral infection, memory CD4+ T cells predominantly used residence to survey nonlymphoid tissues, albeit not as stringently as observed for CD8+ T cells. In contrast, memory CD4+ T cells were more likely to be resident within lymphoid organs than CD8+ T cells. Migration properties of memory-phenotype CD4+ T cells in non-SPF parabionts were similar, generalizing these results to diverse infections and conditions. CD4+ and CD8+ TRM shared overlapping transcriptional signatures and location-specific features, such as granzyme B expression in the small intestine, revealing tissue-specific and migration property-specific, in addition to lineage-specific, differentiation programs. Functionally, mucosal CD4+ TRM reactivation locally triggered both chemokine expression and broad immune cell activation. Thus, residence provides a dominant mechanism for regionalizing CD4+ T cell immunity, and location enforces shared transcriptional, phenotypic, and functional properties with CD8+ T cells.