Antigen presentation to Th1 but not Th2 cells by macrophages results in nitric oxide production and inhibition of T cell proliferation: Interferon-gamma is essential but insufficient

The induction and role of nitric oxide (NO) during antigen presentation by macrophages to T helper (Th) cell subsets was examined. When cultured with Th1 clones, macrophage APC produced NO only in the presence of cognate Ag, which in turn suppressed T cell proliferation. IFN-gamma production by the activated Th1 cells was essential for the induction of NO. Th2 cells presen ted with the same cognate Ag did not induce NO production and proliferated uninhibited. Coactivation of Th1 and Th2 cells specific for the same Ag ind icated that Th2 cells did not inhibit NO production, but were sensitive to NO induced by stimulated Th1 cells. Antigenic activation of Th2 cells in th e presence of rIFN-gamma resulted in NO-mediated inhibition of proliferatio n. Th2 cells provided only a cell-associated cofactor, whereas Th1 cells se creted a soluble cofactor for IFN-gamma as well, i.e., TNF-alpha. Finally, a role for IFN-gamma and NO during immune responses was studied in spleen c ells obtained from immunized IFN-gamma (-/-) mice. NO production and subseq uent inhibition of Ag-specific proliferation ex vivo was observed only afte r the addition of rIFN-gamma. These studies suggest an IFN-dependent regula tory role for NO during Ag-specific Th cell activation involving macrophage s, with obvious implications for Th subset-dependent immune responses in ge neral. (C) 2000 Academic Press.