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to Elaborate TGF-
-Based Suppression1
* Division of Immunology, University of Connecticut Health Center, Farmington, CT 06032; Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92121; Immunomodulation Research Center, University of Ulsan, Ulsan, Republic of Korea; and Department of Surgery, and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329
We identified a murine peptide-specific CD8 T regulatory cell population able to suppress responding CD4 T cells. Immunization with OVA, poly(I:C), and anti-4-1BB generated a population of SIINFEKL-specific CD8 T regulatory cells that profoundly inhibited peptide-responding CD4 T cells from cellular division. The mechanism of suppression required IFN-
, but IFN- alone was not sufficient to suppress the responding CD4 T cells. The data show that CD8 T regulatory cells were unable to suppress unless they engaged IFN-. Furthermore, even in the absence of recall with peptide, the CD8 T regulatory cells suppressed CD4 responses as long as IFN- was present. To examine the effector mechanism of suppression, we showed that neutralizing TGF-
inhibited suppression because inclusion of anti-TGF- rescued the proliferative capacity of the responding cells. TGF--based suppression was dependent completely upon the CD8 T regulatory cells being capable of binding IFN-. This was the case, although peptide recall of primed IFN- –/– or IFN-R–/– CD8 T cells up-regulated pro-TGF- protein as measured by surface latency-associated peptide expression but yet were unable to suppress. Finally, we asked whether the CD8 T regulatory cells were exposed to active TGF- in vivo and showed that only wild-type CD8 T regulatory cells expressed the TGF--dependent biomarker CD103, suggesting that latency-associated peptide expression is not always congruent with elaboration of active TGF-. These data define a novel mechanism whereby IFN- directly stimulates CD8 T regulatory cells to elaborate TGF--based suppression. Ultimately, this mechanism may permit regulation of pathogenic Th1 responses by CD8 T regulatory cells.
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