TGF-BETA IS IMPORTANT IN DETERMINING THE IN-VIVO PATTERNS OF SUSCEPTIBILITY OR RESISTANCE IN MICE INFECTED WITH CANDIDA-ALBICANS

Resistance and susceptibility of mice to systemic infection with the f ungus Candida albicans are associated with the preferential expansion of Th1 and Th2 cells, respectively. In this study, endogenous producti on of TGF-beta was found to be increased soon after infection of heale r mice with a live vaccine strain of the fungus, but downregulated in nonhealer mice with virulent yeast challenge. Although not affecting t he outcome of primary challenge, serologic ablation of TGF-beta in the former animals abrogated development of acquired resistance and resul ted in impaired production of IL-12/IFN-gamma and higher expression of IL-4/IL-10 at the time of reinfection with virulent yeast. A CD4(+) p opulation expressing the memory phenotype, CD44(high)MEL-14(low), whic h appeared to be expanded by yeast infection of nonhealer mice, was si milarly increased in the healer mice by anti-TGF-beta treatment. In vi tro rTGF-beta impaired the candidacidal function of IFN-gamma-activate d macrophages. Yet in nonhealer mice infected with virulent C. albican s, administration of rTGF-beta delayed progression of the disease, whi ch was concomitant with the detection of lower levels of IL-4. In addi tion to previous evidence for an obligatory role of IFN-gamma and IL-1 2 in Candida-driven Th1 cell differentiation in vivo, the present data establish TGF-beta as a third cytokine,the presence of which may be r equired for optimal Th1 development leading to long-lived anticandidal resistance.