Interleukin‐7 activates human naive CD4+ cells and primes for interleukin‐4 production

Abstract

Interleukin (IL)‐4 is considered to be essential for T helper (Th)2 cell development, yet in areas of primary T cell activation, CD4⁺ cells are its only source. This implies that other signals must drive the initial expression of IL‐4 production. The role of CD28 co‐stimulation in Th2 subset development has been described. However, in mice deficient for CD28, Th2 responses are diminished, but not abrogated. Cytokines produced within the lymphoid tissue, e.g. IL‐7, may be important in the primary activation of naive CD4⁺ cells. We have found that human naive CD4⁺ cells purified from umbilical cord blood express the IL‐7 receptor and respond vigorously to IL‐7 during primary stimulation. Naive CD4⁺ cells grown in IL‐4, in the presence or absence of IL‐2, fail to produce Th2 cytokines upon restimulation. In contrast, IL‐7 induces development of a population of T cells that produce large amounts of IL‐4. Growth in IL‐7 also increases IL‐2‐induced production of interferon (IFN)‐γ and IL‐10 production. IL‐7‐induced IL‐4 production is not inhibited by neutralizing antibodies to IL‐4 on its receptor. This implies that IL‐7 acts directly to induce Th2 subset development and not by up‐regulating either production of IL‐4 during culture or expression of the IL‐4 receptor. Moreover, IL‐7 potentiates the effects of CD28 co‐stimulation on both naive CD4⁺ cell proliferation and subsequent IL‐4 production. Following primary stimulation, CD4⁺ cells lose expression of the IL‐7 receptor, resulting in IL‐7 unresponsiveness. This work reveals a novel role for IL‐7 in the primary activation of CD4⁺ cells. We propose that in conjunction with CD28 co‐stimulation, IL‐7 induces the initial expression of IL‐4 production and that IL‐4 acts subsequently to expand Th2 cytokine‐producing cells at the appropriate anatomical site.