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Induction of IL-10 Suppressors in Lung Transplant Patients by CD4⁺25⁺ Regulatory T Cells through CTLA-4 Signaling¹

Ankit Bharat^*, Ryan C. Fields^*, Elbert P. Trulock, G. Alexander Patterson^*, and Thalachallour Mohanakumar^2,*,

^* Department of Surgery, Department of Pathology, Division of Cardiothoracic Surgery, and Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110

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 (T_IL-10 cells) with low IL-2-, IFN--, IL-5-, and no IL-4-producing T cells. These T_IL-10 cells were distinct from Tregs because they lacked constitutive expression of both CD25 and Foxp3. Expansion of T_IL-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 T_IL-10 cells with a concomitant increase in IFN- producing Th1 cells (TIFN- cells). A Transwell culture of col-V-specific T_IL-10 cells with Th1 cells (those generated in absence of Tregs) from the same patient resulted in marked inhibition of IFN- and proliferation of T_IFN- cells, which was reversed by neutralizing IL-10. Furthermore, the T_IL-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 T_IL-10 cells and an increase in T_IFN- 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" T_IL-10 cells.

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 Grant HL56643 (to T.M.). R.F. is recipient of the International Society for Heart and Lung Transplantation Research Fellowship Award.

² Address correspondence and reprint requests to Dr. Thalachallour Mohanakumar, Washington University School of Medicine, Department of Surgery, Box 8109-3328 Clinical Sciences Research Building, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address: kumart{at}wustl.edu

³ Abbreviations used in this paper col-V, collagen V; BOS, bronchiolitis obliterans syndrome; DC, dendritic cell; LT, lung transplant; MMP, metalloproteinase; spm, spots per million cells; Treg, regulator T cell; T_IFN- cell, IFN--producing Th1 cell; T_IL-10 cell, IL-10-producing CD4⁺ T cell.

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