1α,25(OH)2D3 Inhibits Not Only Th1 But Also Th2 Differentiation in Human Cord Blood T Cells

Abstract

(M.P., M.W.) Human naive CD4 ϩ T helper (Th) and CD8 ϩ cytotoxic (Tc) T cells, which only produce IL-2, may differentiate into Th1/Tc1-or Th2/Tc2-like lymphocytes, characterized by their cytokine production profile. 1␣,25-dihydroxyvitamin D 3 (1␣,25(OH) 2 D 3 ) has been reported to inhibit Th1/Tc1-related, but increase Th2/ Tc2-associated cytokines in T cells from adults. In industrialized countries, vitamin D supplementation for prevention of rickets is initiated within the first days of life and continued throughout the entire first year. Epidemiologic studies suggest an association of vitamin D exposure in newborns with the incidence of allergic diseases in later life. This study addresses the effects of 1␣,25(OH) 2 D 3 on Th1/Tc1 versus Th2/Tc2 differentiation in long term cell cultures of (naive) cord blood T lymphocytes. Our results show that in CD4 ϩ as well as CD8 ϩ cord blood cells, 1␣,25(OH) 2 D 3 inhibits not only IL-12-generated IFN-␥ production, but also suppresses IL-4 and IL Human naive T cells, which produce only IL-2, can differentiate into at least two functionally distinct subsets of memory or effector T cells, which can be distinguished by their cytokine profile (1, 2): CD4 ϩ Th1 cells on one hand producing predominantly IFN-␥, IL-2, and lymphotoxin, and CD4 ϩ Th2 cells on the other hand, which are the main source of IL-4 and IL-5, represent two extremely polarized phenotypes of a continuous spectrum of cytokine-producing T lymphocytes. Similar subpopulations (i.e. Tc1 and Tc2) exist in the CD8 ϩ T cell population (3, 4). Th1-and Th2-associated immune responses have been implicated in the pathogenesis of infectious, allergic, and autoimmune diseases (3).The local cytokine environment plays an important role in the differentiation of naive T cells along the Th1/Tc1 or Th2/Tc2 pathway (5, 6). For example, in vitro priming of naive T cells in the presence of IL-4 generates IL-4-producing Th2 effector cells (7-10). Similarly, IL-12, secreted by monocytes and dendritic cells, induces the capacity to produce IFN-␥ in neonatal T cells (11).Furthermore, the arachidonic acid metabolite prostaglandin E2 (12, 13), and several members of the steroid hormone family, such as progesterone (14, 15), glucocorticoids (16), and 1␣,25-dihydroxyvitamin D 3 (1␣,25(OH) 2 D 3 ) (17) have been reported to influence Th and Tc subset generation. 1␣,25(OH) 2 D 3 is not only required for normal mineral homeostasis but also regulates differentiation, growth, and function of different cell types such as hematopoietic and immune cells as well as a variety of normal and malignant epithelial cells (18 -20). The discovery of the high affinity receptor for 1␣,25(OH) 2 D 3 in monocytes and activated lymphocytes (21) suggested that this steroid acts as an immunoregulatory hormone (22,23). Interference with cytokine production of monocytes and lymphocytes seems to be a key mechanism by which 1␣,25(OH) 2 D 3 interacts with the immune system. Suppression of mitogen-induced proliferation (24) and inhibition of secretion of IL-1, ...

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