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.
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