Homeostatic cytokines orchestrate the segregation of CD4 and CD8 memory T-cell reservoirs in mice

Memory T cells (T_Ms) have been detected in many tissues but their quantitative distribution remains largely undefined. We show that in mice there is a remarkably biased accumulation of long-term CD4 T_Ms into mucosal sites (mainly gut, especially Peyer patches), and CD8 T_Ms into lymph nodes and spleen (in particular, peripheral lymph nodes [PLNs]). This distinction correlates with their differentiated expression of PLN- and gut-homing markers. CD8 and CD4 T_Ms selectively require the expression of PLN-homing marker CCR7 or gut-homing marker α4β7 for maintenance. PLNs and gut supply CD8 and CD4 T_Ms with their individually favored homeostatic cytokine, IL-15, or IL-7. Cytokine stimulation in turn regulates the different gut-homing marker expression on CD4 and CD8 T_Ms. IL-15 plays a major role in vivo regulating CD8 TMs homing to PLNs. Thus, the reservoir segregation of CD4 and CD8 T_Ms meets their individual needs for homeostatic cytokines and is under feedback control of cytokine stimulation