TCR-independent proliferation and differentiation of human CD4+ T cell subsets induced by cytokines.

Naïve and memory T cells can divide in an antigen-independent manner in vivo maintaining independently a constant pool size. While naïve T cells require TCR tickling by self-MHC for homeostatic proliferation in lymphopenic mice, memory cells do not but respond to cytokines. Human naive and memory CD4+ T cell subsets can be selectively expanded in vitro with different cytokine combinations. Responsiveness of T cells to homeostatic cytokines is associated with the differentiation state. Thus, while memory cells respond directly to IL-7 and IL-15, naïve T cells require costimulation by dendritic cell-derived cytokines, and selectively respond to IL-4. This differential cytokine responsiveness is associated with the expression and modulation of the relevant cytokine receptors. Cytokine-driven proliferation is independent of TCR-stimulation and shows distinct signal transduction requirements. While cytokine-expanded naive T cells maintain a naive phenotype, memory cells differentiate acquiring new effector functions and switching expression of chemokine receptors. Thus human naïve and memory T cell pools can be maintained with homeostatic cytokines in the absence of TCR stimulation.