Induction of IL-10 Suppressors in Lung Transplant Patients by CD4+25+ Regulatory T Cells through CTLA-4 Signaling

Abstract

T cell-mediated autoimmunity to collagen V (col-V), a sequestered yet immunogenic self-protein, can induce chronic lung allograft rejection in rodent models. In this study we characterized the role of CD4+CD25+ regulatory T cells (Tregs) in regulating col-V autoimmunity in human lung transplant (LT) recipients. LT recipients revealed a high frequency of col-V-reactive, IL-10-producing CD4+ T cells (TIL-10 cells) with low IL-2-, IFN-γ-, IL-5-, and no IL-4-producing T cells. These TIL-10 cells were distinct from Tregs because they lacked constitutive expression of both CD25 and Foxp3. Expansion of TIL-10 cells during col-V stimulation in vitro involved CTLA-4 on Tregs, because both depleting and blocking Tregs with anti-CTLA4 F(ab′)2 mAbs resulted in loss of TIL-10 cells with a concomitant increase in IFN-γ producing Th1 cells (TIFN-γ cells). A Transwell culture of col-V-specific TIL-10 cells with Th1 cells (those generated in absence of Tregs) from the same patient resulted in marked inhibition of IFN-γ and proliferation of TIFN-γ cells, which was reversed by neutralizing IL-10. Furthermore, the TIL-10 cells were HLA class II restricted because blocking HLA class II on APCs resulted in the loss of IL-10 production. Chronic lung allograft rejection was associated with the loss of Tregs with a concomitant decrease in TIL-10 cells and an increase in TIFN-γ cells. We conclude that LT patients have col-V-specific T cells that can be detected in the peripheral blood. The predominant col-V-specific T cells produce IL-10 that suppresses autoreactive Th1 cells independently of direct cellular contact. Tregs are pivotal for the induction of these “suppressor” TIL-10 cells.

Soluble CD30 levels as a diagnostic marker for bronchiolitis obliterans syndrome following human lung transplantation

“…We have shown that BOS+ patients develop early post-transplant inflammation which may activate allo-as well as auto-immunity (18). Further, loss of regulatory T cells which down regulate both auto as well as alloimmunity, may lead to increased immune response leading to the immunopathogenesis of BOS (19). Our finding that sCD30 levels are elevated several months prior to clinical onset of BOS strongly suggests activation of the immune response leading to an increase in the serum sCD30 levels.…”

Th-17, Monokines, Collagen Type V, and Primary Graft Dysfunction in Lung Transplantation

“…Therefore, we must consider the unique collaboration that exists between human memory Th-17 cells and CD14 1 macrophages as a possible link between adaptive and innate immunity. Bharat and colleagues, using PBMCs from patients who had received a lung transplant, demonstrated a key role for immune regulation by CD4 1 CD25 1 T-regulatory cells in preventing outgrowth of col(V)-reactive Th-1 (IFN-g) effector cells in long-term cultures (31,32). However, this report did not address the mechanisms of T-effector function in vivo or the role of IL-17.…”

α1-Antitrypsin monotherapy induces immune tolerance during islet allograft transplantation in mice

“…As shown, grafts from hAAT-treated mice ( Fig. 4A, representative day 72) exhibit a significantly elevated expression of foxp3, TGF-␤, and cytotoxic T lymphocyte antigen-4 (CTLA-4), representing the expected phenotype of Treg cells (17)(18)(19)(20). In contrast, the expression of these genes was either below detection or terminated early in grafts from albumin-treated mice (days 1, 3, 5, and 7).…”