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TNF- Antagonism Generates a Population of Antigen-Specific CD4⁺CD25⁺ T Cells That Inhibit Protective Immunity in Murine Histoplasmosis¹

Division of Infectious Diseases, Veterans Affairs Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45267

In both humans and mice, treatment with TNF- antagonists is associated with serious infectious complications including disseminated histoplasmosis. The mechanisms by which inhibition of endogenous TNF- 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- contained a higher proportion and number of CD4⁺CD25⁺ cells than controls. This elevation was not observed in IFN-- 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--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- 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- is associated with the induction of a population of regulatory T cells that alter protective immunity in an Ag-specific manner to Histoplasma capsulatum.

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¹ This work was supported by a Merit Review Grant from the Veterans Affairs and National Institutes of Health Grants AI061298, AI34361, and AI42747.

² Address correspondence and reprint requests to Dr. George S. Deepe, Jr., Division of Infectious Diseases, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267. E-mail address: george.deepe{at}uc.edu

³ Abbreviations used in this paper: Treg, regulatory T cell; GITR, glucocorticoid inducible TNFR; i.n., intranasally.