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Increased Natural CD4⁺CD25⁺ Regulatory T Cells and Their Suppressor Activity Do Not Contribute to Mortality in Murine Polymicrobial Sepsis¹

Philip O. Scumpia^*, Matthew J. Delano^*, Kindra M. Kelly, Kerri A. O’Malley^*, Philip A. Efron^*, Priscilla F. McAuliffe^*, Todd Brusko, Ricardo Ungaro^*, Tolga Barker, James L. Wynn^*, Mark A. Atkinson, Westley H. Reeves, Michael J. Clare Salzler and Lyle L. Moldawer^2,*

^* Department of Surgery, Department of Medicine, and Department of Pathology, University of Florida College of Medicine, Gainesville, FL 32610

Regulatory T cells (Tregs), including natural CD4⁺CD25⁺ Tregs and inducible IL-10 producing T regulatory type 1 (T_R1) cells, maintain tolerance and inhibit autoimmunity. Recently, increased percentages of Tregs have been observed in the blood of septic patients, and ex vivo-activated Tregs were shown to prevent polymicrobial sepsis mortality. Whether endogenous Tregs contribute to sepsis outcome remains unclear. Polymicrobial sepsis, induced by cecal ligation and puncture, caused an increased number of splenic Tregs compared with sham-treated mice. Splenic CD4⁺CD25⁺ T cells from septic mice expressed higher levels of Foxp3 mRNA and were more efficient suppressors of CD4⁺CD25^– T effector cell proliferation. Isolated CD4⁺ T cells from septic mice displayed increased intracellular IL-10 staining following stimulation, indicating that T_R1 cells may also be elevated in sepsis. Surprisingly, Ab depletion of total CD4⁺ or CD4⁺CD25⁺ populations did not affect mortality. Furthermore, no difference in survival outcome was found between CD25 or IL-10 null mice and wild-type littermates, indicating that Treg or T_R1-generated IL-10 are not required for survival. These results demonstrate that, although sepsis causes a relative increase in Treg number and increases their suppressive function, their presence does not contribute significantly to overall survival in this model.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants R37 GM-40586 and R01 GM-63041, awarded by the National Institute of General Medical Sciences, U.S. Public Health Service. M.J.D. and K.A.O. were supported by a National Research Service Award Training Fellowship in Burns, Trauma, and Sepsis (T32 GM-08721).

² Address correspondence and reprint requests to Dr. Lyle L. Moldawer, Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610-0286. E-mail address: moldawer{at}surgery.ufl.edu

³ Abbreviations used in this paper: Treg, regulatory T cell; T_R1, type 1 regulatory T cell; GITR, glucocorticoid-induced TNFR; CLP, cecal ligation and puncture.

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