Rheumatoid Arthritis Lowers Threshold for T Cell Activation In
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Unchecked CD70 Expression on T Cells Lowers Threshold for T Cell Activation in Rheumatoid Arthritis This information is current as Won-Woo Lee, Zhi-Zhang Yang, Guangjin Li, Cornelia M. of September 27, 2021. Weyand and Jörg J. Goronzy J Immunol 2007; 179:2609-2615; ; doi: 10.4049/jimmunol.179.4.2609 http://www.jimmunol.org/content/179/4/2609 Downloaded from References This article cites 48 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/179/4/2609.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 27, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology 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 Jo¨rg J. Goronzy3* 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 Downloaded from control T cell autoreactivity. The Journal of Immunology, 2007, 179: 2609–2615. heumatoid arthritis (RA)4 is a systemic inflammatory dis- Ag-presenting function of B cells that take up and present Ag to ease that predominantly manifests in diarthrodial joints, tissue-infiltrating T cells (14). R leading to structural damage of the joint architecture (1, T cell activation is ultimately determined by positive signals 2). The main effector mechanisms causing cartilage degeneration from costimulatory molecules and negative signals from inhibitory http://www.jimmunol.org/ and bony erosion include hyperplasia of synoviocytes; production receptors that are expressed on T cells and bind to ligands on APCs of various cytokines, in particular TNF-␣; and receptor activator of (15–18). The classical example for such a costimulatory pathway NFB ligand-mediated activation of osteoclasts (2–4). The nature is the CD28-CD80/CD86 interaction, which is particularly impor- of the defect upstream of these effector functions is a matter of tant in activating naive T cells (15). Indeed, treatment with debate (1, 5). In one model, the inflammation is considered to be CTLA4-Ig that interferes with this receptor-ligand interaction re- the result of a misguided T cell response. Several lines of indirect duces joint inflammation in RA (13). Another costimulatory path- evidence have supported this notion (2, 6). The major disease- way important for the activation of naive T cells is the stimulation associated genetic risk factor is an HLA-DRB1 polymorphism that of CD27 that recognizes the CD70 molecule (16, 18–20). CD28 ϩ is important for the function of CD4 T cells (7, 8). Also, newly and CD27 are constitutively expressed, and costimulatory activi- by guest on September 27, 2021 defined genetic risk factors, such as CLTA-4 and PTPN22, are ties are controlled by the expression of the ligands CD80/CD86 concerned with T cell physiology (9, 10). Experiments in rheuma- and CD70, all of which are tissue specific and spatially and tem- toid synovium/SCID mouse chimera animal models showed that porally restricted (16, 19, 20). synovial inflammation is strictly T cell dependent (11). Moreover, In addition to CD28 and CD27, which mostly control the acti- many patients show evidence of lymphoid neogenesis in the sy- vation of naive CD4 T cells, a large array of molecules has been novium, which optimizes the recognition of Ag by B and T cells shown to regulate T cell activation. One major variable in deter- (2, 12). Finally, targeting the adaptive immune response has shown mining the profile of regulatory molecules on T cells is the age of therapeutic benefits. The most obvious example is treatment with the individual, or, possibly better stated, the replicative history of CTLA4-Ig, which is effective in RA (13). Also, the success of B the T cell population (2, 21). Many of the receptors that have been cell depletion in the treatment of RA has been attributed to the found to control the function of senescent or end-differentiated T cells are primarily expressed on NK cells. Such molecules include members of the killer Ig-like receptor family, NKG2D, fractalkine receptors, and Ig-like transcripts (21–24). In contrast, regulatory *Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory Uni- versity, Atlanta, GA 30322; and †Division of Hematology, Mayo Graduate School, molecules that are usually associated with T cell function, such as Rochester, MN 55901 CD28, CD27, and CD40L, are frequently lost in such T cells (21). Received for publication January 10, 2007. Accepted for publication June 6, 2007. These changes appear to be of particular importance for the patho- The costs of publication of this article were defrayed in part by the payment of page genesis of RA, a disease of late adulthood with increasing age-related charges. This article must therefore be hereby marked advertisement in accordance incidence (2). Moreover, the adaptive immune system in RA patients with 18 U.S.C. Section 1734 solely to indicate this fact. is preaged with premature appearance of many of these T cell senes- 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). cence markers as compared with age-matched healthy controls (2, 6, 21). Indeed, many of these aberrantly expressed T cell regulatory 2 W.-W.L. and Z.-Z.Y. contributed equally to this work. molecules appear to be functionally important in RA and synovial 3 Address correspondence and reprint requests to Dr. Jo¨rg J. Goronzy, Lowance Cen- ter for Human Immunology, Emory University School of Medicine, 101 Woodruff inflammation. Killer Ig-like receptor 2DS2 has been shown to be a Circle #1003, Atlanta, GA 30322. E-mail address: [email protected] genetic risk factor for extra-articular complications of RA (2, 25). 4 Abbreviations used in this paper: RA, rheumatoid arthritis; 5-Aza-dC, 5-aza-2Ј- NKG2D is expressed on end-differentiated CD4 T cells and provides deoxycytidine; DC, dendritic cell; DNMT, DNA methyltransferase; SLE, systemic a costimulatory signal recognizing a ligand expressed in the synovial lupus erythematosus; TSST, toxic shock syndrome toxin. tissue (22, 26). Similarly, fractalkine receptor is expressed on senes- Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 cent CD4 T cells and communicates with synovial fibroblasts through www.jimmunol.org 2610 CD70 OVEREXPRESSION IN RA the recognition of fractalkine (23). Aberrant expression of regulatory molecules on T cells may, therefore, be an important component en- abling the rheumatic disease process. We hypothesized in this study that comparing the gene expression profiles of CD4ϩCD28ϩ and CD4ϩCD28Ϫ T cells from patients would allow for identifying molecules related to accelerated immune aging in RA and involved in RA pathogenesis. The most striking difference in cell surface molecules identified in the arrays was the overexpression of the CD27 ligand CD70. Data presented in this study show that CD4ϩCD28Ϫ T cells have a defect in down-regulat- ing CD70, which leads to sustained expression after T cell activation. Accordingly, expression of this molecule is increased on peripheral CD4 T cells from RA patients. Aberrant CD70 expression on by- stander T cells lowers the TCR threshold necessary for the induction of primary T cell responses, possibly leading to activation of self- reactive T cells and breaches in tolerance. Therapeutic interventions targeting the expression of CD70 and the CD27-CD70 interaction may, therefore, be of particular benefit for RA patients. FIGURE 1. Preferential expression of CD70 on CD4ϩCD28Ϫ T cells. A, Gene expression in CD4ϩCD28ϩ and CD4ϩCD28Ϫ T cells was com- Downloaded from Materials and Methods pared by Affymetrix GeneChip Hu-95Av2. Among putative regulatory cell Subjects surface receptors, the largest difference was seen for the CD27-CD70 re- ceptor-ligand pair. Data shown are the mean expression levels from three PBMCs were obtained from 22 patients with rheumatoid factor-positive individuals. B, Flow cytometric analysis of CD4ϩ T cell lines confirmed a RA, aged 23–77 years, and 27 healthy volunteers, aged 25–81 years. The ϩ Ϫ ϩ Ϫ ϩ Ϫ CD70 CD27 phenotype for CD4 CD28 T cell lines.