Exposure to T helper 2 cytokines in vivo before encounter with antigen selects for T helper subsets via alterations in antigen-presenting cell function.

The Th1 subset of CD4+ T cells mediate both delayed-type hypersensitivity (DTH) responses and experimental allergic encephalomyelitis (EAE). Th1 cells are induced by immunization of young adult female and older (> or = 10 wk of age) male SJL mice. By contrast, young adult (< or = 8 wk of age) male mice are characterized by the inability of immunization to induce either a DTH response or EAE, demonstrating a clear sex and age dependence to these Th1-mediated responses in SJL mice. T cell activation in age-matched female and male SJL mice was compared to understand the mechanism(s) of these differential responses. Here, we report that immunization of DTH responder female mice primes for Ag-specific secretion of IFN-gamma but not IL-4 and IL-10. In contrast, immunization of DTH nonresponder male mice primes Ag-specific T cells that secrete IL-4 and IL-10, but not IFN-gamma. Depletion of either IL-4 or IL-10 recovers DTH responsiveness in young adult male mice, demonstrating expansion of Th1 cells in these mice when Th2 cytokines are suppressed. The age- and sex-dependent inability to prime Th1 cells in young male mice is due to the functional absence of a macrophage APC population defined by co-expression of Mac-1 and Mac-3. To determine whether Th2 cytokines directly affect the APC's ability to support the priming of Th1 cells, Mac-3+ APC isolated from naive young male donors, which had been depleted of either IL-4 or IL-10, were transferred into DTH nonresponder males. Induction of DTH responses in these recipients demonstrates that in vivo suppression of Th2 cytokines enables the male-derived Mac-3+ APC to support priming of Th1 responses. These data indicate that, in addition to their regulatory roles in controlling preferential T cell subset expansion, exposure of APC to cytokines in vivo before the initial encounter with Ag may regulate induction of CD4+ T cell subsets.