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

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-gamma (IFN-gamma), 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-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-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-gamma-producing cells were enumerated in CD4- CD8- cell fractions. Overall, our results showed that (i) antigen-specific secretion of IFN-gamma 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-gamma, likely released by CD4- CD8- lymphocytes; (iii) a finely regulated IFN-gamma production correlated in the healer mice with IL-12 mRNA detection, and IL-12 was required in vitro for yeast-induced development of IFN-gamma-producing CD4+ cells. Although the mutually exclusive production of IL-4/IL-10 and IFN-gamma by early CD4+ cells may be the major discriminative factor of cure and noncure responses in candidiasis, IL-12 rather than IFN-gamma production may be an indicator of Th1 differentiation.

Primary Role for CD4+T Lymphocytes in Recovery from Oropharyngeal Candidiasis

“…IL-12 is produced by phagocytic cells, B cells, and dendritic cells and acts on T lymphocytes and NK cells by inducing proliferation and production of cytokines, especially IFN-␥. In vivo, IL-12 has been shown to be required for the induction of Th1 responses in systemic candidiasis (41), although its action may also be regulated by IFN-␥ (15). In a model of gastrointestinal candidiasis, both Th1 cytokines, such as IFN-␥, and the Th2 cytokines IL-4 and IL-5 were produced by CD4 ϩ cells from Peyer's patches and mesenteric lymph nodes at a time when the fungus was cleared from the stomach and intestine (16).…”

Deregulated Production of Protective Cytokines in Response toCandida albicansInfection in Patients with Chronic Mucocutaneous Candidiasis

“…However, the complexity of cytokine networks cannot be overemphasized, particularly regarding the roles of IL-12 and IFN-␥ in inducing and mediating Th1 immunity. Consequently, it has been demonstrated that low levels of IL-12 in spite of normal IFN-␥ levels result in progressive Candida infection and death in mice (27). Additionally highlighting the complexity of protective responses to fungi in humans, patients with an IFN-␥-IFN␥R and/or IL-12-IL-12R deficiency did not have overwhelming or chronic fungal infections (24), even though a number of patients had bouts of candidiasis (Casanova, personal communication).…”

Effect of anti-interleukin 12 treatment on murine lyme borreliosis.

“…Nevertheless, the lack of difference in cytokine production by primed CD4 ϩ T cells after in vitro restimulation with B. burgdorferi suggests that the differentiation to a Th1 phenotype in both groups of mice was equivalent. Some reports have indicated that the presence of IL-12 is required for the development of Th1 responses (37,38), while other studies suggest that both IL-12 and IFN-␥ are required (39). Moreover, mouse strain-specific backgrounds can directly influence Th1 development under neutral conditions (40).…”