Infection induces diverse effector T cells that give rise to several distinct subsets of memory T cells: the two major ones being central memory T (TCM) cells and effector memory T (TEM) cells. A new study has shown that expression of CX3C-chemokine receptor 1 (CX3CR1) defines three distinct subsets of effector and memory CD8+ T cells and identifies a new subpopulation that is the main subset that surveys peripheral tissues.
The study was motivated by an observation that CX3CR1 upregulation varies among effector T cells. Detailed analysis of this was carried out using reporter mice in which the gene encoding green fluorescent protein (GFP) was knocked into the Cx3cr1 locus (Cx3cr1+/gfp mice). Starting 5 days after acute infection with lymphocytic choriomeningitis virus, GFP expression was detected and revealed three subsets of effector T cells: CX3CR1hi, CX3CR1mid and CX3CR1−. CX3CR1 expression required cognate antigen recognition and was largely restricted to recently activated CD8+ T cells. The CX3CR1hi subset had a phenotype that was typical of terminally differentiated effector T cells, being CD27−, CD127− and mostly KLRG1+, and containing few interleukin-2 (IL-2)-producing cells. In mice lacking T-bet, which is crucial for terminal differentiation, antigen-activated T cells remained mainly CX3CR1− or CX3CR1mid. The observation that the CX3CR1− subset contained the most polyfunctional cells, producing IL-2, interferon-γ and tumour necrosis factor, suggested that this subset represents the least differentiated cells. Together, their observations suggest a linear sequence of effector T cell differentiation from CX3CR1− to CX3CR1mid to CX3CR1hi.
Next, the authors investigated whether the differential expression of CX3CR1 affects the potential to generate memory populations, by performing adoptive transfer of each effector T cell subset into separate congenic hosts. The three subsets generated markedly different numbers of memory progeny. CX3CR1− effector T cells generated the greatest number of memory offspring, with equal numbers of CX3CR1−, CX3CR1mid and CX3CR1hi memory T cells. CX3CR1mid effector T cells generated mainly CX3CR1mid and CX3CR1hi memory T cells, whereas CX3CR1hi effector T cells generated only CX3CR1hi memory T cells. Further analysis of these memory subsets showed that the CX3CR1mid cells underwent more frequent homeostatic divisions than the other memory T cells, contributing to self-renewal of the CX3CR1mid pool or expanding the CX3CR1− pool.
expression of CX3CR1 delineates two previously undistinguishable subsets of TCM cells
To further define the memory T cell subsets, the authors looked at their ability to home to lymph nodes. The CX3CR1− and CX3CR1mid subsets responded vigorously to the CCR7 ligand CCL19 and were detectable in lymph nodes, whereas the CX3CR1hi cells did not respond to CCL19 or enter lymph nodes. This suggests that the CX3CR1hi subset represents classical TEM cells, and that expression of CX3CR1 delineates two previously undistinguishable subsets of TCM cells (CX3CR1− and CX3CR1mid TCM cells). These TCM cell subsets were further distinguished by differential expression of CD62L, which, together with ligands for CCR7, is required for lymph node homing. CD62L upregulation was more rapid and more frequent among the CX3CR1− TCM cell subset than the CX3CR1mid TCM cell subset. This was consistent with the increased ability of CX3CR1− memory T cells to access lymph nodes compared with CX3CR1mid memory T cells.
The current dogma poses that the TEM cell subset is the main subset responsible for surveying peripheral tissues. However, Gerlach et al. found that CX3CR1hi TEM cells are largely excluded from peripheral tissues. Instead, the CD62L− fraction from the lymph-draining peripheral tissues was dominated by CX3CR1mid TCM cells. Using parabiotic mice, the authors confirmed that the blood-derived CX3CR1mid subset traverses the peripheral tissues and returns to the blood via the lymph, in a CD62L-independent manner.
So, by subdividing CD8+ T cells on the basis of CX3CR1 expression, new subsets with differing phenotypic, homeostatic and migratory properties can be defined.
Gerlach, C. et al. The chemokine receptor CX3CR1 defines three antigen-experienced CD8 T cell subsets with distinct roles in immune surveillance and homeostasis. Immunity http://dx.doi.org/10.1016/j.immuni.2016.10.018 (2016)
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Bird, L. Sorting memories. Nat Rev Immunol 17, 3 (2017). https://doi.org/10.1038/nri.2016.146