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.

Abdelsamed et al. demonstrate that the poised effector potential of human memory CD8 T cells is coupled to maintenance of effector-associated DNA methylation programs during in vitro and in vivo homeostatic proliferation.

DNMT3A deletion preserves CAR T cell functionality during prolonged stimulation.

The pool of beta cell-specific CD8 + T-cells in type 1 diabetes (T1D) sustains an autoreactive potential despite having access to a constant source of antigen. To investigate the long-lived nature of these cells, we established a DNA methylation-based T cell “multipotency index” and found that beta cell-specific CD8 + T-cells retained a stem-like epigenetic multipotency score. Single cell ATAC-seq analysis confirmed the co-existence of naive and effector-associated epigenetic programs in individual beta cell-specific CD8 + T-cells. Assessment of beta cell-specific CD8 + T-cell anatomical distribution and the establishment of stem-associated epigenetic programs revealed that self-reactive CD8 + T-cells isolated from murine lymphoid tissue retained developmentally plastic phenotypic and epigenetic profiles relative to the same cells isolated from the pancreas. Collectively, these data provide new insight into the longevity of beta cell-specific CD8 + T cell responses, and document the utility of this novel methylation-based multipotency index for investigating human and mouse CD8 + T-cell differentiation.

Highlights d CD19-CAR T cells undergo extensive DNA methylation reprogramming during therapy d DNA methylation status of the CAR T cell product can predict in vivo expansion d CD8 + CD19-CAR T cells acquire exhaustion-associated DNA methylation programs d Antigen-positive tumor relapse does not elicit CAR T cell expansion