Keeping T cell memories in mind

Abstract

The mammalian central nervous system (CNS) contains a vibrant community of resident adaptive immune cells at homeostasis. Among these are memory CD8⁺ and CD4⁺ T cells, which reside in the CNS in the settings of health, aging, and neurological disease. These T cells commonly exhibit a tissue-resident memory (T_RM) phenotype, suggesting that they are antigen-experienced and remain separate from the circulation. Despite these characterizations, T cell surveillance of the CNS has only recently been studied through the lens of T_RM immunology. In this Review, we outline emerging concepts of CNS T_RM generation, localization, maintenance, function, and specificity. In this way, we hope to highlight roles of CNS T_RM in health and disease to inform future studies of adaptive neuroimmunity.

Keywords: adaptive immunity; central nervous system; memory CD4 T cell; memory CD8 T cell; neuroimmune interactions; tissue resident memory T cell.

Key Figure:. Current Understanding of Tissue Resident Memory (T_RM) T Cells in the Central Nervous System (CNS) in mice and/or humans

A. Identification. Tissue-localized T_RM can be distinguished from circulating T circulating memory (T_CM) and T effector memory (T_EM) in part by their resistance to labeling via intravenously injected antibodies (IV-) in mice. IV-T_RM in the CNS can be further distinguished from transiently surveilling IV-T_EM through a combination of surface markers and transcription (Tx) factors. B. Generation. Young naïve, specific pathogen free (SPF) mice have low numbers of T_RM in the CNS. In contrast, mice which have experienced infection, immunizations, tumors, or aging exhibit robust populations of T_RM in the CNS. C. Localization. T_RM can seed multiple niches of the murine and/or human CNS including the parenchyma, cerebrospinal fluid (CSF), choroid plexus (ChP), meninges, and cranial nerves (CN) I/II with associated sensory structures. D. Maintenance and Homeostasis. T_RM can communicate with resident glial populations through cytokine and PD-1:PD-L1 signaling [20, 22, 93, 98]. E. Function and Specificity. CNS CD8⁺ and CD4⁺ T_RM can produce cytokines and/or elicit cytolysis that may confer protective or pathological outcomes through TCR-mediated antigen (Ag)-specific recognition processes or bystander activation [13, 25, 26, 41, 59, 69, 71]. This figure was created using BioRender (https://biorender.com/).