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CD4⁺CD25⁺ Regulatory T Cells Protect against Injury in an Innate Murine Model of Chronic Kidney Disease

Deepika Mahajan^*, Yiping Wang^*, Xiahong Qin^*, Ying Wang^*, Guoping Zheng^*, Yuan Min Wang, Stephen I. Alexander and David C.H. Harris^*

^* Centre for Transplantation and Renal Research, The University of Sydney at Westmead Millennium Institute, and Centre for Kidney Research, Children’s Hospital at Westmead, Westmead, Sydney, Australia

Address correspondence to: Dr. Deepika Mahajan, Centre for Transplantation and Renal Research, The University of Sydney at Westmead Millennium Institute, Westmead NSW 2145, Australia. Phone: +61-2-9845-8906; Fax: +61-2-9633-9351; E-mail: deepika_mahajan{at}wmi.usyd.edu.au

Received for publication August 10, 2005. Accepted for publication August 1, 2006.

Studies of mechanisms of disease regulation by CD4⁺CD25⁺ regulatory T cells (Treg) have been focused on their interaction with effector T cells; however, the possibility that regulation might involve noncognate cells has not been explored in detail. This study investigated the effect of CD4⁺CD25⁺ Treg on macrophage proinflammatory properties and phenotype in vitro and found that they modulate macrophages by inhibiting their activation, leading to reduced proinflammatory cytokine production and a downregulated effector phenotype. For testing the in vivo significance of this effect, CD4⁺CD25⁺ T cells that expressed high levels of Foxp3 were reconstituted into SCID mice after induction of Adriamycin nephropathy, a noncognate model of chronic renal disease. CD4⁺CD25⁺ T cells significantly reduced glomerular and interstitial injury. In addition, there was a significant fall in the number of macrophages in both the glomeruli and interstitium of SCID mice that were reconstituted with Treg as compared with the Adriamycin alone group. Blockade of TGF- using neutralizing antibodies significantly impaired the protective effect of Treg. These findings delineate a TGF-–dependent Treg–macrophage inhibitory interaction that can explain cognate-independent protection by Treg.

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