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.

Osteosarcomas are sarcomas of the bone, derived from osteoblasts or their precursors, with a high propensity to metastasize. Osteosarcoma is associated with massive genomic instability, making it problematic to identify driver genes using human tumors or prototypical mouse models, many of which involve loss of Trp53 function. To identify the genes driving osteosarcoma development and metastasis, we performed a Sleeping Beauty (SB) transposon-based forward genetic screen in mice with and without somatic loss of Trp53. Common insertion site (CIS) analysis of 119 primary tumors and 134 metastatic nodules identified 232 sites associated with osteosarcoma development and 43 sites associated with metastasis, respectively. Analysis of CIS-associated genes identified numerous known and new osteosarcoma-associated genes enriched in the ErbB, PI3K-AKT-mTOR and MAPK signaling pathways. Lastly, we identified several oncogenes involved in axon guidance, including Sema4d and Sema6d, which we functionally validated as oncogenes in human osteosarcoma.

Extracellular ATP (eATP) is an ancient 'danger signal' used by eukaryotes to detect cellular damage. In mice and humans, the release of eATP during inflammation or injury stimulates both innate immune activation and chronic pain through the purinergic receptor P2RX7. It is unclear, however, whether this pathway influences the generation of immunological memory, a hallmark of the adaptive immune system that constitutes the basis of vaccines and protective immunity against re-infection. Here we show that P2RX7 is required for the establishment, maintenance and functionality of long-lived central and tissue-resident memory CD8 T cell populations in mice. By contrast, P2RX7 is not required for the generation of short-lived effector CD8 T cells. Mechanistically, P2RX7 promotes mitochondrial homeostasis and metabolic function in differentiating memory CD8 T cells, at least in part by inducing AMP-activated protein kinase. Pharmacological inhibitors of P2RX7 provoked dysregulated metabolism and differentiation of activated mouse and human CD8 T cells in vitro, and transient P2RX7 blockade in vivo ameliorated neuropathic pain but also compromised production of CD8 memory T cells. These findings show that activation of P2RX7 by eATP provides a common currency that both alerts the nervous and immune system to tissue damage, and promotes the metabolic fitness and survival of the most durable and functionally relevant memory CD8 T cell populations.

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.