Interleukin‐12 but not interferon‐γ production correlates with induction of T helper type‐1 phenotype in murine candidiasis

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Abstract
By means of polymerase chain reaction‐assisted mRNA amplification, we have monitored message levels of interleukin (IL)‐12 in splenic macrophages and of interferon‐γ (IFN‐γ), IL‐4, and IL‐10 in CD4+ and 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 (“nonhealer mice”). The timing and pattern of message detection did not differ qualitatively by the expression of IFN‐γ 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‐12p40 was readily detected in macrophages from healer mice but was detected only early in infection in mice with progressive disease. Cytokine levels were measured in sera, and antigen‐driven cytokine production by CD4+ and CD8+ cells was assessed in vitro, while IFN‐γ‐producing cells were enumerated in CD4− CD8− cell fractions. Overall, our results showed that (i) antigen‐specific secretion of IFN‐γ protein 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‐γ, likely released by CD4− CD8− lymphocytes; (iii) a finely regulated IFN‐γ production correlated in the healer mice with IL‐12 mRNA detection, and IL‐12 was required in vitro for yeast‐induced development of IFN‐γ‐producing CD4+ cells. Although the mutually exclusive production of IL‐4/IL‐10 and IFN‐γ by early CD4+ cells may be the major discriminative factor of cure and noncure responses in candidiasis, IL‐12 rather than IFN‐γ production may be an indicator of Th1 differentiation.