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B7H1-Ig Fusion Protein Activates the CD4⁺ IFN- Receptor⁺ Type 1 T Regulatory Subset through IFN--Secreting Th1 Cells¹

Qing Ding^2,*, Liming Lu^2,*, Baolong Wang^*, Yun Zhou^*,, Yang Jiang^*, Xiaorong Zhou^*, Lijun Xin^*, Zhijun Jiao^* and Kuang-Yen Chou^3,*,

^* Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China; and E-Institute of Shanghai Universities, Immunology Division, Shanghai, China

It has been demonstrated in our previous work that, in the human skin-grafting model, the expression of costimulatory molecule B7H1 (PD-L1) by keratinocytes plays an essential role in inducing local tolerance via activation of IL-10-secreting T cells. This study further analyzes the role of B7H1 in differentiation of type 1 T regulatory (Tr1) cells and explores underlying mechanisms. Mouse fusion protein B7H1-Ig is used, together with immobilized anti-CD3 mAb, to costimulate the purified naive CD4⁺ T cells. B7H1-Ig-treated CD4⁺ T cells were found to activate a characteristic Tr1 population possessing a CD4⁺CD25^–Foxp3^– CD45RB^low phenotype. These regulatory T cells strongly inhibited the Th1-dominated MLR by secretion of IL-10 and TGF-. Moreover, B7H1-treated Tr1 cells also resulted in suppressed clinical scores and demyelination when adoptively transferred into mice with experimental allergic encephalomyelitis. Furthermore, analysis of the cytokine profile indicated that there were two differential reaction patterns during the B7H1-Ig-induced Tr1 development. These two patterns were characterized by activation of IFN-R⁺IL-10R^– Th1 and IFN-R⁺IL-10R⁺ Tr1 cells, respectively. Secretion of IFN- by Th1 and the expression of IFN-R on Tr1 were critical for further Tr1 differentiation, as demonstrated by mAb blocking and by analysis in IFN-^–/– mice. In conclusion, B7H1 is capable of inducing Tr1 differentiation from naive CD4⁺ T cells by coactivation in an IFN-- or Th1-dependent manner. Our study may shed some light upon the clinical usage of B7H1 as a therapeutic reagent for induction of tolerance.

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 study was supported by grants from the Natural Science Foundation of China (30530690), the National Key Basic Research Program of China (2003AA205009, 2001CB 510003), and the Foundation of Shanghai Sci-Tech Council (03JC14085, 05DZ19734).

² Q.D. and L.L. contributed equally to this work as first authors.

³ Address correspondence and reprint requests to Dr. Kuang-Yen Chou, Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China. E-mail address: my{at}shsmu.edu.cn or kychoumy{at}yahoo.com

⁴ Abbreviations used in this paper: Treg, T regulatory; Tr1, type 1 Treg; DC, dendritic cell; EAE, experimental allergic encephalomyelitis; LN, lymph node; MOG, myelin oligodendrocyte glycoprotein; Nrp1, Neuropilin-1; RR, relative response; rmIL-2, mouse rIL-2.

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