Chemokine receptor expression identifies pre-Th1, pre-Th2 and non-polarized cells among human CD4⁺ central memory T cells

Jens Geginat, PhD

Institute for Research in Biomedicine (IRB), Via Vela 6, CH-6500 Bellinzona, Switzerland.

E-mail: jens.geginat@irb.unisi.ch

Cental memory T cells (T_CM) express lymph node homing receptors CCR7 and CD62L are largely devoid of effector functions but acquire characteristics of effector memory cells (T_EM, i.e. CCR7^- Th1 or Th2) following stimulation with TCR agonists or homeostatic cytokines. Here we show that three chemokine receptors identify functional subsets within the human CD4⁺ T_CM pool. T_CM expressing CXCR3 secreted low amounts of IFN-g, whereas CCR4⁺ T_CM produced some IL-4, but not IL-5. In response to IL-7 and IL-15 CXCR3⁺ T_CM and CCR4⁺ T_CM invariably generated fully differentiated CCR7^- Th1 and Th2 cells, respectively, suggesting that they represent pre-Th1 and pre-Th2. Conversely, CXCR5⁺ T_CM lacking CXCR3 and CCR4 remained non-polarized and retained CCR7 and CD62L expression upon cytokine-driven expansion. Unlike naïve cells all memory subsets had a low TREC content, spontaneously incorporated BrdU ex vivo and contained cells specific for tetanus toxoid. Conversely, recall responses to CMV and vaccinia virus were largely restricted to CXCR3⁺ T_CM and T_EM. We conclude that antigen-specific memory T cells are distributed between T_EM and different subsets of T_CM. Our results also explain how the quality of primary T cell responses could be maintained by T_CM in the absence of antigen.