Chronic CD70-Driven Costimulation Impairs IgG Responses by Instructing T Cells to Inhibit Germinal Center B Cell Formation through FasL-Fas Interactions 1 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 * 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 Journal of Immunology, 2009, 183: 6442– 6451. T he development of neutralizing Abs is crucial in estab- lishing pathogen clearance after primary infection and provides immediate and long-lasting protection against reinfection with the same pathogen. Upon Ag encounter, Ag-spe- cific B cells start proliferating and subsequently differentiate into plasma cells that generally produce specific Abs of low affinity. However, some B cells initiate the formation of germinal centers where affinity maturation of Abs takes place. Germinal centers contain follicular dendritic cells that present Ags to B cells, and follicular helper T cells that provide help through CD40L-CD40 signaling and cytokines. Ag and CD4 T cell help is limiting, thereby enabling the selective outgrowth of B cells with high af- finity for Ag and differentiation of these B cells into long-lived plasma cells that produce high-affinity Abs (1–3). Neutralizing Abs develop poorly and late after infection with chronic viruses such as hepatitis C virus (HCV) 3 (4, 5) and HIV-1 (6 – 8) and also after experimental infection of mice with persisting strains of lymphocytic choriomeningitis virus (LCMV) (9). Sev- eral factors contribute to the inefficient induction of neutralizing Abs such as low immunogenicity of viral structures (10), low pre- cursor frequency of virus-specific B cells (11), and induction of T cell-driven immune pathology (9, 12, 13). CD4 T cells induce polyclonal B cell activation and hypergammaglobulinemia in chronic LCMV infection at the cost of the effective generation of neutralizing Abs (12). Also, CD8 T cells are involved in down- regulation of B cell responses in chronic LCMV infection, as CD8- deficient mice, or mice in which CD8 T cells have been depleted with Abs display induction of neutralizing Ab production (9, 13). Under homeostatic conditions, B cell follicles contain very low numbers of CD8 T cells, and the function of these CD8 T cells is unclear (14). In contrast, during chronic infection, such as in HIV-1 infected patients, CD8 T cells appear to accumulate within the B cell follicles (15). This indicates that cross-talk of not only CD4 but also CD8 T cells with B cells takes place in chronic infection and that this results in shutdown of effective B cell responses. Several diseases characterized by chronic infection or chronic inflammation, such as HIV-1 or chronic LCMV infection (16, 17), systemic lupus erythematosus (18), or rheumatoid arthritis (19), are accompanied by constitutive up-regulation of CD70 expres- sion. CD70 is a molecule of the TNF superfamily that promotes proliferation and acquisition of effector function of T cells after binding CD27. Constitutive expression of transgenic CD70 on B cells (20), dendritic cells (21) or T cells (22) results in extensive formation and accumulation of effector T cells, in vivo. The role of chronic CD70 and CD27 signaling in the regulation of B cell re- sponses through costimulation of T cells is unsettled. To study the impact of constitutive costimulation through CD70 and CD27 on the ability of T cells to modulate B cell responses, we used CD70- transgenic (Tg) mice. Previously, we have shown that reverse sig- naling through CD70 in B cells strengthens IgM Ab responses but *Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands; and † Bioceros BV, Utrecht, The Netherlands Received for publication May 20, 2009. Accepted for publication September 18, 2009. 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, Uni- versity of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. E-mail address: k.p.vangisbergen@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. Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 The Journal of Immunology www.jimmunol.org/cgi/doi/10.4049/jimmunol.0901565