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Unchecked CD70 Expression on T Cells Lowers Threshold for T Cell Activation in Rheumatoid Arthritis¹

Won-Woo Lee^2,*, Zhi-Zhang Yang^2,, Guangjin Li^*, Cornelia M. Weyand^* and Jörg J. Goronzy^3,*

^* Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory University, Atlanta, GA 30322; and Division of Hematology, Mayo Graduate School, Rochester, MN 55901

Rheumatoid arthritis (RA) is characterized by premature immune aging with accumulation of degenerate T cells deficient for CD28. Gene expression profiling of CD4⁺CD28^– and CD4⁺CD28⁺ T cells to discover disease-promoting activities of CD28^– T cells identified expression of CD70 as a most striking difference. Hence, CD70 was significantly more expressed in CD4 T cells from RA patients compared with age-matched controls (p < 0.006). The underlying mechanism was a failure to repress CD70 expression after activation-dependent induction. This defect in RA was not related to differential promoter demethylation. CD70 on bystander CD4⁺CD28^– T cells functioned by lowering the threshold for T cell activation; admixture of CD4⁺CD28^– T cells augmented TCR-induced responses of autologous naive CD4⁺CD28⁺ T cells, particularly of low-avidity T cells. The data support a model in which CD70 expressed on T cells causes degeneracy in T cell responses and undermines tolerance mechanisms that normally control T cell autoreactivity.

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 funded in part by grants from the National Institutes of Health (RO1 AR AR42527, RO1 AR 41974, and RO1 AI 44142).

² W.-W.L. and Z.-Z.Y. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Jörg J. Goronzy, Lowance Center for Human Immunology, Emory University School of Medicine, 101 Woodruff Circle #1003, Atlanta, GA 30322. E-mail address: jgoronz{at}emory.edu

⁴ Abbreviations used in this paper: RA, rheumatoid arthritis; 5-Aza-dC, 5-aza-2'-deoxycytidine; DC, dendritic cell; DNMT, DNA methyltransferase; SLE, systemic lupus erythematosus; TSST, toxic shock syndrome toxin.

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