The Chemokine Receptor CX3CR1 Defines Three Antigen-Experienced CD8 T Cell Subsets with Distinct Roles in Immune Surveillance and Homeostasis

Abstract

SUMMARY Infections induce pathogen-specific T cell differentiation into diverse effectors (TEff) that give rise to memory (TMem) subsets. The cell fate decisions and lineage relationships that underlie these transitions are poorly understood. Here, we found that the chemokine receptor CX3CR1 identifies three distinct CD8+ TEff and TMem subsets. Classical central (TCM) and effector memory (TEM) cells and their corresponding TEff precursors were CX3CR1− and CX3CR1high, respectively. Viral infection also induced a numerically stable CX3CR1int subset that represented ~15% of blood-borne TMem cells. CX3CR1int TMem cells underwent more frequent homeostatic divisions than other TMem subsets and not only self-renewed, but also contributed to the expanding CX3CR1− TCM pool. Both TCM and CX3CR1int cells homed to lymph nodes, but CX3CR1int cells, and not TEM cells, predominantly surveyed peripheral tissues. As CX3CR1int TMem cells present unique phenotypic, homeostatic and migratory properties, we designate this subset peripheral memory (TPM) cells and propose that TPM cells are chiefly responsible for the surveillance of non-lymphoid tissues.

Repeated Antigen Exposure Extends the Durability of Influenza-Specific Lung-Resident Memory CD8+ T Cells and Heterosubtypic Immunity

“…For this purpose, we evaluated expression of CD103, CD69 (classical T rm markers) (Schenkel and Masopust, 2014; Wu et al, 2014), Eomes (a key transcription factor downregulated in T rm ) (Mackay et al, 2015), CX3CR1 (expressed by T rm precursors) (Gerlach et al, 2016), and CXCR3 (facilitates homing to the lung/airway) (Slütter et al, 2013 ) on 1°M and 4°M P14 generated in the same host (Figures S2A and S2C). Overall, we observed no substantial difference in selected phenotypic characteristics between 1°M and 4°M lung T rm .…”

A primary role for human central memory cells in tissue immunosurveillance

“…[3][4][5][6]15 The role of T CM in immunosurveillance has been assumed to be limited to patrolling the lymph nodes for evidence of pathogen exposure. The initial description of human T CM characterized these cells as having poor effector functions and little tissue tropism.…”

“…1,2 In mice and nonhuman primates, T CM provide effective long-term protection because they persist long term in the circulation, have a high proliferative potential, and can give rise to both effector and effector memory T cells (T EM ) after antigen reencounter. [3][4][5][6] Although they can be drawn into inflamed tissues, T CM have not been identified in animals as providing primary tissue-based immunosurveillance. 7 We report that human T CM express tissue-homing receptors, are found in noninflamed human tissues, and have potent effector functions, supporting a role for these cells in primary tissue immunosurveillance.…”

Enzymatic synthesis of core 2 O-glycans governs the tissue-trafficking potential of memory CD8 + T cells

“…In fact, it has recently been reported that circulating T cells exhibiting a T CM phenotype can be identified in human skin (38), demonstrating that T CM are not confined to the circulation and lymph nodes, but likely traffic into non-lymphoid tissues. A recent study by Gerlach et al found that the T CM /T EM classification also does not accurately predict the homeostatic trafficking patterns of memory CD8 + T cells (39). Notably, the authors found that CX3CR1 Hi /CD62L Lo /CD27 Lo T EM CD8 + T cells were not present in lymph collected from the thoracic duct, suggesting that these cells were, in fact, confined to the circulation.…”