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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901565v1 183/10/6442    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Beishuizen, C. R. L. Articles by van Gisbergen, K. P. J. M. PubMed PubMed Citation Articles by Beishuizen, C. R. L. Articles by van Gisbergen, K. P. J. M.

Chronic CD70-Driven Costimulation Impairs IgG Responses by Instructing T Cells to Inhibit Germinal Center B Cell Formation through FasL-Fas Interactions¹

Cathrien R. L. Beishuizen,^* Natasja A. M. Kragten,^* Louis Boon, Martijn A. Nolte,^* Rene A. W. van Lier,^* and Klaas P. J. M. van Gisbergen^2*

^*Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands; and Bioceros BV, Utrecht, The Netherlands

CD70 provides costimulation that enhances effector T cell differentiation upon binding of its receptor, CD27. During chronic immune activation, CD70 is constitutively expressed on activated immune cells, and this induces T cell-driven disruption of neutralizing Ab responses via an unknown mechanism. We used CD70-transgenic mice to investigate the effect of constitutive expression of CD70 on T cell-dependent B cell responses. CD70 induced up-regulation of the B cell follicle homing chemokine receptor CXCR5 on T cells, enabling not only CD4 but also CD8 T cells to infiltrate the B cell follicles. CD70-transgenic mice failed to develop productive germinal center formation and displayed impaired IgG Ab responses. Defective germinal center B cell differentiation was critically dependent on CD70-mediated CD27 signaling in T cells, and involved Fas-dependent impairment of germinal center B cell differentiation. Thus, CD70-driven costimulation enables T cells to terminate B cell responses, thereby compromising durable Ab production. Our findings imply that the CD70- and CD27-driven costimulatory axis may be involved in shutdown of B cell responses before clearance of Ag. Because CD70 is expressed constitutively in chronic viral infections such as HIV-1 infection, this mechanism may also contribute to defects in humoral immunity associated with this disease.

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 supported by Vidi and Vici grants of The Netherlands Organization for Scientific Research.

² Address correspondence and reprint requests to Dr. Klaas P. J. M. van Gisbergen, Department of Experimental Immunology, K0-132, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. E-mail address: k.p.vangisbergen{at}amc.nl

³ Abbreviations used in this paper: HCV, hepatitis C virus; EM, effector memory; LCMV, lymphocytic choriomeningitis virus; med LN, mediastinal lymph node; mes LN, mesenteric lymph node; Tg, transgenic; GC, germinal center; WT, wild type; PNA, peanut agglutinin; TNP-KLH, trinitrophenyl-keyhole limpet hemocyanin.