INTERLEUKIN-12 BUT NOT INTERFERON-GAMMA PRODUCTION CORRELATES WITH INDUCTION OF T-HELPER TYPE-1 PHENOTYPE IN MURINE CANDIDIASIS

By means of polymerase chain reaction-assisted mRNA amplification, we have monitored message levels of interleukin (IL)-12 in splenic macrop hages and of interferon-gamma (IFN-gamma), IL-4, and IL-10 in CD4(+) a nd CD8(+) T cells using Candida albicans/host combinations that result either in a T helper type-1 (Th1)-associated self-limiting infection (''healer mice'') or in a Th2-associated progressive disease (''nonhea ler mice''). The timing and pattern of message detection did not diffe r qualitatively by the expression of IFN-gamma or IL-10 mRNA in CD4(+) and CD8(+) cells from healer (i.e. PCA-2 into CD2F1) vs. nonhealer (i .e. CA-6 into CD2F1 or PCA-2 into DBA/2) mice. In contrast, IL-4 mRNA was uniquely expressed by CD4(+) cells from nonhealer animals. IL-12p4 0 was readily detected in macrophages from healer mice but was detecte d only early in infection in mice with progressive disease. Cytokine l evels were measured in sera, and antigen-driven cytokine production by CD4(+) and CD8(+) cells was assessed in vitro, while IFN-gamma-produc ing cells were enumerated in CD4(-) CD8(-) cell fractions. Overall, ou r results showed that (i) antigen-specific secretion of IFN-gamma prot ein in vitro by CD4(+) cells occurred only in healing infection; (ii) IL-4- and IL-10-producing CD4(+) cells would expand in nonhealer mice in the face of high levels of circulating IFN-gamma, likely released b y CD4(-) CD8(-) lymphocytes; (iii) a finely regulated IFN-gamma produc tion correlated in the healer mice with IL-12 mRNA detection, and IL-1 2 was required in vitro for yeast-induced development of IFN-gamma-pro ducing CD4(+) cells. Although the mutually exclusive production of IL- 4/IL-10 and IFN-gamma by early CD4(+) cells may be the major discrimin ative factor of cure and noncure responses in candidiasis, IL-12 rathe r than IFN-gamma, production may be an indicator of Th1 differentiatio n.