CYTOKINE AND NITRIC-OXIDE REGULATION OF THE IMMUNOSUPPRESSION IN TRYPANOSOMA-CRUZI INFECTION

An intense suppression of splenic T cell proliferation to mitogens and to Ags from the parasite is characteristic of the acute phase of Tryp anosoma cruzi infection in mice, The impairment of proliferation is co incident with high levels of IFN-gamma and nitrite and decreased produ ction of IL-2 in the supernatants of spleen cell cultures from infecte d mice, Previous work demonstrated that suppression of proliferation i s largely mediated by the population of adherent cells in the infected spleen. In this study we confirmed the active suppression exerted by these cells on Con A, anti-CD3, and parasite Ag-stimulated proliferati on of CD4(+) splenic T cells. Inasmuch as the high production of IFN-g amma and of nitrite were compatible with intense macrophage activation and nitric oxide (NO) production, we determined the effects of cytoki nes that regulate macrophage activation and of NO on the proliferation of spleen cells from infected mice. We show that spleen cell prolifer ation to Ag and to T cell polyclonal stimuli is increased by neutraliz ing mAbs to IFN-gamma, TNF-alpha and -beta, or by the inhibitor of NO synthase, N-G-monomethyl-L-arginine, added to the cultures. The additi on of rIL-2 or rIL-4 also contributed to suppression reversal, and the combined addition of rIL-2 and anti-IFN-gamma mAb further increased l ymphocyte proliferation. Anti-IL-4, anti-IL-10, or anti-TGF-beta neutr alizing mAbs did not modify suppressed proliferative responses, and th e addition of rIL-10 or of rTGF-beta also did not recover cell prolife ration. Thus, the suppression of proliferative responses in T. cruzi-i nfected mice resulted largely from increased NO production by macropha ges activated by IFN-gamma and TNF allied to insufficient IL-2 to full y support in vitro growth of T lymphocytes.