TNF-alpha antagonism generates a population of antigen-specific CD4+CD25+ T cells that inhibit protective immunity in murine histoplasmosis

• Published in: The Journal of immunology (1950) 2008-01, Vol.180 (2), p.1088-1097
• Main Authors: Deepe, Jr, George S, Gibbons, Reta S
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Antibodies, Monoclonal - pharmacology; CD4 Antigens - analysis; Histoplasmosis - immunology; Immunity - drug effects; Interleukin-10 - metabolism; Interleukin-2 Receptor alpha Subunit - analysis; Mice; Mice, Inbred Strains; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - transplantation; Tumor Necrosis Factor-alpha - antagonists & inhibitors
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.180.2.1088

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 of regulatory T cells that alter protective immunity in an Ag-specific manner to Histoplasma capsulatum.