Repression of Cyclic Adenosine Monophosphate Upregulation Disarms and Expands Human Regulatory T Cells

Matthias Klein et al., 2012. J Immunol. 188:1091-1097.

Speaker: Ming-Zhang Lin (林明璋)                              Time: 15:10~16:00, Oct. 31, 2012

Commentator: Dr. Bei-Chang Yang (楊倍昌老師)      Place: Room 601

Abstract

CD4+CD25+Foxp3+ regulatory T cells (Tregs) can suppress other immune cells and, thus, are critical mediators of peripheral self-tolerance that avert autoimmune disease and allergies. On the other hand, Tregs can prevent immune reactions against tumors and pathogens. Despite the importance of Tregs, the molecular mechanisms of suppression remain incompletely understood and controversial. Previous studies have described that murine Treg increase their intracellular level of the second messenger cAMP upon activation and consign this potent immunosuppressive compound via gap junctions in vitro and in vivo into other cells. Within the responder cell, cAMP inhibits proliferation and differentiation, including IL-2 production. Although these findings have been confirmed and extended for murine Treg by several groups, the role of cAMP in human Treg function has only been partially addressed. In this study want to investigated the extrinsic and intrinsic functions of cAMP production in human Treg in detail. To better understand the extrinsic and intrinsic function of cAMP upregulation in Treg, they interfered with cAMP upregulation by blocking adenylyl cyclase (AC) activity with the cell-permeable, irreversible AC inhibitor MDL-12. Pretreatment of Treg with MDL-12 completely prevented the increase in intracellular cAMP upon activation and significantly impaired Treg suppressive activity but favors Treg proliferation and also induces NFATc1/Aa re-expression. The author used Graft-versus-host disease (GVHD) module to analyzed the importance of cAMP generation for human Treg-mediated suppression in vivo. Nevertheless, when human Treg were pretreated with MDL-12 and engrafted together with syngenichuman PBMC, cAMP repression also abrogated their protective activity in vivo. These findings clearly demonstrate that AC activity and the resulting increase in intracellular cAMP are essentially required for the suppressive capacity of human Treg in vivo.

References:

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2.      Bopp, T et al., Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. 2007. J. Exp. Med. 204: 1303–1310.