Chemokine Receptor Expression Identifies Pre–T Helper (Th)1, Pre–Th2, and Nonpolarized Cells among Human CD4+ Central Memory T Cells

We previously reported that central-memory T cells (T(CM) cells), which express lymph node homing receptors CCR7 and CD62L, are largely devoid of effector functions but acquire characteristics of effector-memory T cells (T(EM) cells) (i.e., CCR7(-) T helper [Th]1 or Th2 cells) after stimulation with T cell receptor agonists or homeostatic cytokines. Here we show that three chemokine receptors identify functional subsets within the human CD4(+) T(CM) cell pool. T(CM) cells expressing CXCR3 secreted low amounts of interferon gamma, whereas CCR4(+) T(CM) cells produced some interleukin (IL)-4, but not IL-5. In response to IL-7 and IL-15, CXCR3(+) T(CM) and CCR4(+) T(CM) cells invariably generated fully differentiated CCR7(-) Th1 and Th2 cells, respectively, suggesting that they represent pre-Th1 and pre-Th2 cells. Conversely, CXCR5(+) T(CM) cells lacking CXCR3 and CCR4 remained nonpolarized and retained CCR7 and CD62L expression upon cytokine-driven expansion. Unlike naive cells, all memory subsets had a low T cell receptor rearrangement excision circle content, spontaneously incorporated bromodeoxyuridine ex vivo, and contained cells specific for tetanus toxoid. Conversely, recall responses to cytomegalovirus and vaccinia virus were largely restricted to CXCR3(+) T(CM) and T(EM) cells. We conclude that antigen-specific memory T cells are distributed between T(EM) cells and different subsets of T(CM) cells. Our results also explain how the quality of primary T cell responses could be maintained by T(CM) cells in the absence of antigen.