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 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.
Romani
L
L
Department of Experimental Medicine, University of Perugia, Italy.
Mencacci
A
A
Tonnetti
L
L
Spaccapelo
R
R
Cenci
E
E
Wolf
S
S
Puccetti
P
P
Bistoni
F
F
D000818:Animals; D001483:Base Sequence; D002177:Candidiasis / Q000276:immunology*; D002478:Cells, Cultured; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D018664:Interleukin-12; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D007378:Interleukins; D012333:RNA, Messenger; D018664:Interleukin-12; D007371:Interferon-gamma