2 research outputs found
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Identification and characterization of tissue-resident memory T cells in humans
Memory T cells are critical for maintaining lifelong immunity by protecting against reinfection with previously encountered pathogens. In recent years, a subset of memory T cells termed tissue-resident memory T cells (TRM) has emerged as the primary mediator of protection at many tissue sites. Numerous studies in mice have demonstrated that TRM accelerate pathogen clearance compared with other subsets of memory T cells. The defining characteristic of TRM is that they are retained within tissues and do not circulate in the blood. The lack of TRM in blood has proved to be a barrier for investigating the role of TRM in healthy humans. As a result, there are many outstanding questions about TRM biology in humans, including which phenotypic markers identify TRM, if TRM represent a unique memory subset, as well as defining transcriptional and functional characteristics of this subset.
Through a unique collaboration with the local organ procurement agency, we obtained samples from >15 tissue sites from healthy organ donors of all ages. We found that the surface marker CD69 was expressed by memory CD4+ and CD8+ T cells in multiple tissues including spleen and other lymphoid tissues, lung, and intestines, but not in blood, suggesting that this marker may identify TRM in human tissues. We identify a core transcriptional signature that distinguishes CD69+ memory T cells in tissues from CD69- memory T cells in tissues and blood with key homologies to the transcriptional profile of TRM in mice, suggesting that CD69 expression identifies TRM in humans. We show that human TRM have a distinct profile of adhesion and migration markers, and a unique dual functional capacity encompassing effector cytokine production but also the upregulation of inhibitory markers and the ability to produce IL-10 upon stimulation. These results suggest unique adaptations for TRM to maintain long-term residence within tissues and carry out pathogen clearance.
We found substantial heterogeneity within human TRM in lymphoid and mucosal tissue sites, including a substantial fraction (40-60%) of TRM in various human tissues with the ability to efflux fluorescent dyes. These efflux(+) TRM had phenotypic and transcriptional characteristics associated with quiescence, including expression of immunomodulatory markers, reduced expression of exhaustion markers, and reduced turnover at steady state. Upon TCR stimulation, efflux(+) TRM produced lower levels of proinflammatory cytokines and cytotoxic molecules but had a superior ability to proliferate compared with efflux(-) TRM. However, efflux(+) also had an enhanced capacity for IL-17 production along with transcriptional features of IL-17 signaling following stimulation. Overall, these studies establish universal properties of human TRM and hint at the function of distinct TRM subsets in mediating tissue immunity
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Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites
Tissue-resident memory T cells (TRMs) in mice mediate optimal protective immunity to infection and vaccination, while in humans, the existence and properties of TRMs remain unclear. Here, we use a unique human tissue resource to determine whether human tissue memory T cells constitute a distinct subset in diverse mucosal and lymphoid tissues. We identify a core transcriptional profile within the CD69+ subset of memory CD4+ and CD8+ T cells in lung and spleen that is distinct from that of CD69− TEM cells in tissues and circulation and defines human TRMs based on homology to the transcriptional profile of mouse CD8+ TRMs. Human TRMs in diverse sites exhibit increased expression of adhesion and inhibitory molecules, produce both pro-inflammatory and regulatory cytokines, and have reduced turnover compared with circulating TEM, suggesting unique adaptations for in situ immunity. Together, our results provide a unifying signature for human TRM and a blueprint for designing tissue-targeted immunotherapies