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Protein Processing and Activity through TCR Triggering of Primary CD8+ T Regulatory Cells1
* Department of Immunology, University of Connecticut Health Center, Farmington, CT 06032; and
Department of Surgery and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329
In general, TGF
is synthesized as a procytokine that requires proteolytic activation, release of the mature cytokine from its noncovalently associated latent-associated peptide, and binding to TGFRII to mediate suppressive activity. We tracked this process in mice containing primed CD8 regulatory T cells (Tregs) by immunoblotting in primary whole cell lysates for pro-TGF, latent-associated peptide and mature TGF. Generation of CD8 Tregs promoted processing of the 50 kDa pro-TGF protein into a 12.5 kDa mature TGF species in vivo. Despite the inability to detect mature TGF in the sera of mice with primed CD8 Tregs and in the synthetic culture medium of stimulated CD8 Tregs, we demonstrated engagement of TGFRII through immunoblotting for Smad2 phosphorylation. This process relied on continual TCR triggering, which also induced Smad3 phosphorylation. To understand the movement of mature TGF, we showed that in contrast to IFN-
, mature TGF does not remain a soluble cytokine but is likely to be rapidly adsorbed by neighboring cells. These data show the exquisite local control directed toward TGF by the immune system and underscore the fine specificity involved in its detection.
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 National Institutes of Health Grants AI 142858 and AI 52108 (to A.T.V.).
2 Address correspondence and reprint requests to Dr. Anthony T. Vella, Department of Immunology-MC1319, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06032. E-mail address: vella{at}uchc.edu
3 Abbreviations used in this paper: Treg, T regulatory cell; LAP, latent-associated peptide; poly(IC), polyinosinic-polycytidylic acid; Imm lysate, lymphoid populations (as described in text); LN, lymph node.
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