Regulatory T Cells Sequentially Migrate from Inflamed Tissues to Draining Lymph Nodes to Suppress the Alloimmune Response

Abstract

To determine site and mechanism of suppression, regulatory T cell (Treg) migration and function were investigated in an islet allograft model. Treg first migrated from blood to the inflammed allografts, this depended on CCR2, CCR4, CCR5, and P- and E-selectin ligands, and was essential for suppression of alloimmunity. In the allograft, Treg were activated, upregulated effector molecules, migrated to the draining lymph nodes (dLN) in a CCR2, CCR5, and CCR7 fashion, and this movement was essential for optimal suppression. Treg inhibited dendritic cell migration in a TGFβ and IL-10 dependent fashion; and suppressed antigen specific T effector cell migration, accumulation, and proliferation in dLNs and allografts. These results showed that sequential migration from blood to the target tissue and then to dLNs were required for nTreg to differentiate and execute fully their suppressive function, by inhibiting DC in the peripheral tissue, and T effector cell responses in dLN and allografts.

Regulatory T cells inhibit acute IFN-γ synthesis without blocking T-helper cell type 1 (Th1) differentiation via a compartmentalized requirement for IL-10

“…13, does not necessarily disrupt Th1 differentiation: The effector pool was fully able to mount an IFN-γ response when removed from the Tregs. Our data are consistent with the need for Tregs to be present both in the lymph node and the infected/inflamed tissue for full regulatory activity (7)(8)(9)(10). Thus, we support a model in which Tregs regulate developing immunity centered around acute regulation of cytokines (Fig.…”

“…The variety of mechanisms Tregs can use provides the potential to disable a CD4 + T-cell during initial activation, proliferation, differentiation, and effector function (4)(5)(6). Full regulatory function in vivo also requires the presence of Tregs in both the draining lymphoid nodes and the inflamed tissue (7)(8)(9)(10). Specific IL-10 ablation in Tregs led to dysregulated immunity at barrier surfaces such as the lung, gut, and skin (11), suggesting Treg effector mechanisms may be context dependent.…”

Real-time immune cell interactions in target tissue during autoimmune-induced damage and graft tolerance

“…These results suggest that in this experimental setting, the two different immune outcomes (graft protection or damage) are probably not caused by a difference in the numbers of T eff cells expanded during the priming phase. Alternatively, the results highlighted the critical requirement of sufficient recruitment of T reg cells to the inflammatory site and the continuous presence of T reg cells for optimal suppression, as suggested in previous studies with models of autoimmune oophoritis (Samy et al, 2005), islet transplantation (Zhang et al, 2009), and other models of immune-mediated (Tisch and Wang, 2008;Shevach, 2011).…”

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

“…Unlike CD8 + effector cells, FoxP3 + T Reg cells require LN occupancy and CCR7 signaling for their activation and function [78][79][80]. T Reg cells sequentially migrate between peripheral tissues and LNs to both inhibit DC migration from the periphery as well as prevent effector T cell migration, activation and proliferation [81]. In the inflamed peripheral tissues, T Reg cells are activated, secrete transforming growth factor β and interleukin 10 (IL-10) and then migrate to the draining LN in a CCR7-dependent manner [81].…”

“…T Reg cells sequentially migrate between peripheral tissues and LNs to both inhibit DC migration from the periphery as well as prevent effector T cell migration, activation and proliferation [81]. In the inflamed peripheral tissues, T Reg cells are activated, secrete transforming growth factor β and interleukin 10 (IL-10) and then migrate to the draining LN in a CCR7-dependent manner [81]. Upon reaching the LN, T Reg cells preferentially migrate to the paracortex where they interact with CD8α + DCs and tissue derived CD11b − CD8α − DCs [82].…”