Interleukin-7 activates human naive CD4+ cells and primes for interleukin-4 production.
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)-gamma 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.
Webb
L M
LM
Kennedy Institute of Rheumatology, London, GB.
Foxwell
B M
BM
Feldmann
M
M
D015703:Antigens, CD / Q000502:physiology; D018106:CD28 Antigens / Q000502:physiology*; D017252:CD3 Complex / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000096:biosynthesis*; D015851:Interleukin-7 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D018123:Receptors, Interleukin / Q000502:physiology; D020395:Receptors, Interleukin-7; D018418:Th2 Cells / Q000276:immunology*; D014470:Umbilical Cord
D015703:Antigens, CD; D018106:CD28 Antigens; D017252:CD3 Complex; D007376:Interleukin-2; D015851:Interleukin-7; D018123:Receptors, Interleukin; D020395:Receptors, Interleukin-7; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma