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

CD4 T cell localization impacts function and differentiation. Beura et al. show that memory CD4+ T cells are largely resident in both lymphoid and non-lymphoid tissues, organize local recall responses, and share overlapping transcriptional and location-specific features with CD8+ TRM.

Interferon beta (IFNβ) 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. Here we demonstrate that in both mouse and human T cells, IFNβ specifically inhibits the production of IL-2 upon T cell receptor (TCR) engagement without affecting other cytokines or activation markers. Rather than disrupting TCR signaling, IFNβ 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 IFNβ and consequent recruitment of histone deacetylases (HDACs) to the IL-2 promoter. In accordance, ablation of CREM expression or inhibition of HDAC activity eliminates the suppressive effects of IFNβ on IL-2 production. Collectively, these findings provide a molecular basis by which IFNβ limits T cell responses.

Central memory T (TCM) cells patrol lymph nodes and perform conventional memory responses upon re-stimulation: 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, TEM, and TRM cells upon recall. Ex-TRM cells, former intestinal TRM that rejoined the circulating pool, heritably maintained a predilection for homing back to their tissue of origin upon subsequent reactivation and a heightened capacity to re-differentiate into TRM cells. Thus, TRM cells can rejoin the circulation but are advantaged to re-form local TRM when called upon.