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.

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.

The spleen is one of the major immunological sites for maintaining blood homeostasis. Previous studies showed that heterogeneous splenic macrophage populations contribute in complimentary ways to control blood-borne infections and induce effective immune responses. Marginal metallophilic macrophages (MMMΦs) and marginal zone macrophages (MZMΦs) are cells with great ability to internalize blood-borne pathogens such as virus or bacteria. Their localization adjacent to T- and B-cell-rich splenic areas favors the rapid contact between these macrophages and cells from adaptive immunity. Indeed, MMMΦs and MZMΦs are considered important bridges between innate and adaptive immunity. Although red pulp macrophages (RpMΦs) are mainly considered scavengers for senescent erythrocytes, several data indicate a role for RpMΦs in control of infections such as blood-stage malaria as well as in the induction of innate and adaptive immunity. Here, we review current data on how different macrophage subsets recognize and help eliminate blood-borne pathogens, and, in turn, how the inflammatory microenvironment in different phases of infection (acute, chronic, and after pathogen clearance) influences macrophage function and survival.

Tissue-resident memory (Trm) CD8 + T cells mediate protective immunity in barrier tissues, but the cues promoting Trm cell generation are poorly understood. Sensing of extracellular adenosine triphosphate (eATP) by the purinergic receptor P2RX7 is needed for recirculating CD8 + T cell memory, but its role for Trm cells is unclear. Here we showed that P2RX7 supported Trm cell generation by enhancing CD8 + T cell sensing of TGF-b, which was necessary for tissue residency. P2RX7-deficient Trm cells progressively decayed in nonlymphoid tissues and expressed dysregulated Trm-specific markers. P2RX7 was required for efficient reexpression of the receptor TGF-bRII through calcineurin signaling. Forced Tgfbr2 expression rescued P2RX7-deficient Trm cell generation, and TGF-b sensitivity was dictated by P2RX7 agonists and antagonists. Forced Tgfbr2 also rescued P2RX7-deficient Trm cell mitochondrial function. Sustained P2RX7 signaling was required for long-term Trm cell maintenance, indicating that P2RX7 signaling drives induction and CD8 + T cell durability in barrier sites.

Of course I also have to thank the members of the Center for Immunology, the MICaB program, and the Jamequist lab. This has been an incredible environment to work in for the past five years. I consider myself incredibly lucky to have had the opportunity to complete my PhD here. To the members of the Jamequist lab (past and present), thank you for the insightful scientific discussions, camaraderie, and for being such good friends. Your thoughtful criticisms and generosity with your time has been instrumental in my success. In particular, Drs.