T-CELL AND NON-T CEL COMPARTMENTS CAN INDEPENDENTLY DETERMINE RESISTANCE TO LEISHMANIA-MAJOR

In experimental murine cutaneous leishmaniasis caused by Leishmania ma jor (Lm), the cellular determinants governing development of protectiv e or exacerbative T cells are not well understood. We, therefore, atte mpted to determine the influence of T cell and non-T cell compartments on disease outcome. To this end, T cell chimeric mice were constructe d using adult thymectomized lethally irradiated, bone marrow-reconstit uted (ATXBM) animals of genetically resistant, C57BL/6, or susceptible , BALB/c, backgrounds. These hosts were engrafted with naive T cell po pulations from H-2-congenic susceptible, BALB.B6-H-2(b), or resistant, C57BL/6.C-H-2(d), animals, respectively. Chimeric mice were then infe cted with Lm, and disease outcome was monitored. BALB/c T cell chimeri c mice, BALB/c ATXBM hosts given naive C57BL/6.C-H-2(d) T cells, resol ved their infections as indicated by reductions in both lesion size an d parasite numbers. Furthermore, the mice developed typical Th1 (inter feron [IFN]-gamma(hi)interleukin[IL]-4(lo)) cytokine patterns. In cont rast, both sham chimeric, BALB/c ATXBM hosts given naive BALB/c T cell s, and control irradiated euthymic mice succumbed to infection, produc ing Th2 profiles (IFN-gamma(lo)IL-4(hi)IL-10(hi)). C57BL/6 T cell chim eras, C57BL/6 ATXBM hosts given naive BALB.B6-H-2(b) T cells, resolved their infections as did C57BL/6 sham chimeras and euthymic controls. Interestingly, whereas C57BL/6 control animals produced Th1 cytokines, chimeric animals progressed from ThO (IFN-gamma(hi)IL-4(hi)IL-10(hi)) to Th2 (IFN-gamma(lo)IL-4(hi)IL-10(hi)) cytokine profiles as cure ens ued. Both reconstitution and chimeric status of all mice were confirme d by flow cytometry. In addition, T cell receptor V beta usage of Lm-s pecific blasts was determined. In all cases, V beta use was multiclona l, involving primarily V beta 2, 4, 6, 8.1, 8.2, 8.3, 10, and 14, with relative V beta frequencies differing between H-2(b) and H-2(d) anima ls. Most importantly, however, these differences did not segregate bet ween cure and noncure outcomes. These findings indicate that: (a) gene tic traits determining cure in Lm infection can direct disease outcome from both T cell and non-T cell compartments; (b) the presence of the curing genotype in only one compartment is sufficient to confer cure; (c) curing genotype T cells autonomously assume a Th1 cytokine profil e-mediating cure; (d) noncuring genotype T cells can mediate cure in a curing environment, despite the onset of Th2 cytokine production; and lastly, (e) antigen specificity of responding T cells, as assessed by V beta T cell receptor diversity, is not a critical determinant of di sease outcome.