Journal
JOURNAL OF IMMUNOLOGY
Volume 180, Issue 2, Pages 1088-1097Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.180.2.1088
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Funding
- NIAID NIH HHS [AI42747, R37 AI042747, AI34361, AI061298, P01 AI061298-020003, R37 AI042747-10, R01 AI034361, P01 AI061298] Funding Source: Medline
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In both humans and mice, treatment with TNF-alpha antagonists is associated with serious infectious complications including disseminated histoplasmosis. The mechanisms by which inhibition of endogenous TNF-alpha alter protective immunity remain obscure. Herein, we tested the possibility that neutralization of this cytokine triggered the emergence of T cells that dampen immunity. The lungs of mice given mAb to TNF-alpha contained a higher proportion and number of CD4(+)CD25(+) cells than controls. This elevation was not observed in IFN-gamma- or GM-CSF-deficient mice or in those given a high inoculum. Phenotypic analysis revealed that these cells lacked many of the characteristics of natural regulatory T cells, including Foxp3. CD4(+)CD25(+) cells from TNF-alpha-neutralized mice suppressed Ag-specific, but not nonspecific, responses in vitro. Elimination of CD25(+) cells in vivo restored protective immunity in mice given mAb to TNF-alpha and adoptive transfer of CD4(+)CD25(+) cells inhibited immunity. In vitro and in vivo, the suppressive effect was reversed by mAb to IL-10. Thus, neutralization of TNF-alpha is associated with the induction of a population regulatory T cells that alter protective immunity in an Ag-specific manner to Histoplasma capsulatum.
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