We have focused our studies in a number of different areas in FY2016: 1. For several years we have been interested in the role of cell surface and secreted TGF-beta in Treg Function. TGF-beta can have pleotropic effects on different cell types ranging from immune suppression, the promotion of fibrosis, and the promotion/suppression of tumor growth. Activated Treks, but not activated T conventional (Tconv) cells, express the leucine rich repeat protein, GARP, which is responsible for surface localization of latent TGF-beta1. Although TGF-beta1 has been implicated in the suppressor function of Tregs, Treg conditional knock outs of TGF-beta1 or GARP display normal suppressor function in vitro. Cell surface associated TGF-beta1 on Treg cells may also mediate immunoregulatory functions. We postulated that one cell intrinsic role of the GARP/L-TGF-beta1 complex may be to provide active TGF-beta1 for the induction of pTregs during the induction of oral tolerance. We demonstrated in an adoptive transfer model that recipient Tregs play a non-redundant role in the induction of Foxp3+ pTreg following the oral administration of antigen. This result is in contrast to the view that CD103+ DCs are the source of TGF-beta1. The contribution of recipient Treg to pTreg induction was mediated by TGF-beta1 derived from the GARP/L-TGF-beta1 complex on the recipient Tregs, as pTreg induction was impaired when the recipient Treg cells could not produce TGF-beta1 or failed to express GARP. The induction of oral tolerance was normal in animals whose Treg were deficient in integrin beta8. It is therefore likely that TGF-beta1 derived from the GARP/L-TGF-1 complex is activated by integrin beta8 expressed by CD103+ DC. 2. In general, all the proposed mechanisms for Treg function postulate that once Tregs are activated via the TCR, the suppressor-effector mechanism they utilize is non-specific. We addressed this question by asking whether iTregs specific for one antigen could suppress the activation/expansion of naive T cells specific for a distinct antigen when both were simultaneously expressed by the same DCs. iTregs specific for one antigen suppressed the activation of naive T cells specific for their cognate antigen, but had no effect on the activation of naive T cells specific for a different antigen expressed on the same DC. We therefore explored alternative mechanisms by which iTregs might mediate suppressor function. Analysis of iTreg-DC co-cultures in vitro using flow cytometry and confocal microscopy demonstrated that specific peptide-MHCII complexes were captured, expressed on the cell surface, and internalized by iTregs leaving DCs with decreased levels of antigen. Polyclonal iTregs, naive, and activated antigen-specific Teff cells did not capture peptide MHCII complexes. These studies suggest that antigen-specific iTreg inhibit immune responses locally in an antigen-specific fashion by forming firm interactions with DCs leading to a stripping of peptide-MHCII complexes from the DC.

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Akkaya, Billur; Holstein, Amanda H; Isaac, Christopher et al. (2017) Ex-vivo iTreg differentiation revisited: Convenient alternatives to existing strategies. J Immunol Methods 441:67-71
Shevach, Ethan M (2017) Garp as a therapeutic target for modulation of T regulatory cell function. Expert Opin Ther Targets 21:191-200
Vermeersch, Elien; Denorme, Frederik; Maes, Wim et al. (2017) The role of platelet and endothelial GARP in thrombosis and hemostasis. PLoS One 12:e0173329
Akkaya, Billur; Miozzo, Pietro; Holstein, Amanda H et al. (2016) A Simple, Versatile Antibody-Based Barcoding Method for Flow Cytometry. J Immunol 197:2027-38
Edwards, Justin P; Hand, Timothy W; Morais da Fonseca, Denise et al. (2016) The GARP/Latent TGF-?1 complex on Treg cells modulates the induction of peripherally derived Treg cells during oral tolerance. Eur J Immunol 46:1480-9
Ujiie, Hideyuki; Shevach, Ethan M (2016) ?? T Cells Protect the Liver and Lungs of Mice from Autoimmunity Induced by Scurfy Lymphocytes. J Immunol 196:1517-28
Edwards, Justin P; Thornton, Angela M; Shevach, Ethan M (2014) Release of active TGF-?1 from the latent TGF-?1/GARP complex on T regulatory cells is mediated by integrin ?8. J Immunol 193:2843-9
Chattopadhyay, Gouri; Shevach, Ethan M (2013) Antigen-specific induced T regulatory cells impair dendritic cell function via an IL-10/MARCH1-dependent mechanism. J Immunol 191:5875-84
Edwards, Justin P; Fujii, Hodaka; Zhou, Angela X et al. (2013) Regulation of the expression of GARP/latent TGF-?1 complexes on mouse T cells and their role in regulatory T cell and Th17 differentiation. J Immunol 190:5506-15
Davidson, Todd S; Shevach, Ethan M (2011) Polyclonal Treg cells modulate T effector cell trafficking. Eur J Immunol 41:2862-70

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