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Increased CD4⁺Foxp3⁺ T Cells in BAFF-Transgenic Mice Suppress T Cell Effector Responses

Immunology and inflammation Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

The cytokine B cell activation factor of the TNF family (BAFF) is considered to perform a proinflammatory function. This paradigm is particularly true for B cell-dependent immune responses; however the exact role for BAFF in regulating T cell immunity is ill-defined. To directly assess the effect of BAFF upon T cells, we analyzed T cell-dependent immune responses in BAFF-transgenic (Tg) mice. We found that T cell responses in BAFF-Tg mice are profoundly compromised, as indicated by their acceptance of islet allografts and delayed skin graft rejection. However, purified BAFF-Tg effector T cells could reject islet allografts with a normal kinetic, suggesting that the altered response did not relate to a defect in T cell function per se. Rather, we found that BAFF-Tg mice harbored an increased number of peripheral CD4⁺Foxp3⁺ T cells. A large proportion of the BAFF-expanded CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Tregs) were CD62L^lowCD103^high and ICAM-1^high, a phenotype consistent with an ability to home to inflammatory sites and prevent T cell effector responses. Indeed, depletion of the endogenous BAFF-Tg Tregs allowed allograft rejection to proceed, demonstrating that the increased Tregs were responsible for preventing alloimmunity. The ability of BAFF to promote Treg expansion was not T cell intrinsic, as Tregs did not express high levels of BAFF receptor 3, nor did excessive BAFF trigger NF-B2 processing in Tregs. In contrast, we found that BAFF engendered Treg expansion through an indirect, B cell-dependent mechanism. Thus, under certain conditions, BAFF can play a surprising anti-inflammatory role in T cell biology by promoting the expansion of Treg 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 Address correspondence and reprint requests to Dr. Shane T. Grey, Gene Therapy & Autoimmunity Group, Immunology and Inflammation Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia. E-mail address: s.grey{at}garvan.org.au

² Abbreviations used in this paper: BAFF, B cell-activating factor of the TNF family; BR3 (also known as BAFFR), BAFF receptor 3; DTH, delayed-type hypersensitivity; Treg, regulatory T cell; Tg, transgenic; mBSA, mouse BSA; WT, wild type; MST, mean survival time; GITR, glucocorticoid-induced TNFR.

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The JI 2009 182: 739-740. [Full Text]  

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