Proliferation and differentiation potential of human CD8(+) memory T-cell subsets in response to antigen or homeostatic cytokines

Four human CD8(+) T-cell subsets, naive (CCR7(+)CD45RA(+)), central memory (T-CM, CCR7(+)CD45RA(-)), effector memory (T-EM, CCR7(-)CD45RA(-)), and CD45RA(+) effector memory cells (T-EMRA, CCR7(-)CD45RA(+)) were compared for their capacity to proliferate and differentiate in response to antigen or homeostatic cytokines. Cytokine responsiveness and interleukin-15 receptor expression were low in naive T cells and progressively increased from T-CM to T-EM and T-EMRA. In contrast, the capacity to accumulate in response to T-cell receptor (TCR) or cytokine stimulation showed a reciprocal pattern and was associated with resistance to cell death and Bcl-2 expression. Whereas all TCA-stimulated cells acquired a CD45RA(-)CCR7(-) phenotype, cytokine-stimulated cells maintained their phenotype with the exception of T-CM cells, which expressed CCR7, CD45RA, and perforin in various combinations. Single CD8(+) T-CM cells, but not TEM cells, could be expanded with cytokines, and the obtained clones displayed several distinct phenotypes, suggesting that T-CM cells are heterogeneous. Consistently, CCR4 expression in the CD8(+) T-CM pool discriminated CCR4(+) type 2 polarized cells (Tc2) and CCF14(-)CTL precursors. Finally, ex vivo bromodeoxyuridine (BrdU) incorporation experiments revealed that memory subsets have different in vivo proliferation rates, with CCR4(-)T(CM) having the highest turnover and TEMRA the lowest. These results show that human CD8(+) memory T-cell subsets have different proliferation and differentiation potentials in vitro and in vivo. Furthermore, they suggest that TEMRA cells are generated from a T-CM subset upon homeostatic prollferation in the absence of antigen.