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* Department of Immunology and
Department of Medical Biophysics, Faculty of Medicine, University of Toronto;
Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, Toronto, Ontario, Canada;
Interdisciplinary Research Center of Autoimmune Diseases and Department of Medical Sciences, University of Eastern Piedmont, Novara, Italy; and
¶ Division of Molecular Immunology, La Jolla Institute of Allergy and Immunology, La Jolla, CA 92037
Germinal center (GC) responses to T-dependent Ags require effective collaboration between Th cells, activated B cells, and follicular dendritic cells within a highly organized microenvironment. Studies using gene-targeted mice have highlighted nonredundant molecules that are key for initiating and maintaining the GC niche, including the molecules of the ICOS, CD40, and lymphotoxin (LT) pathways. Signaling through ICOS has multiple consequences, including cytokine production, expression of CD40L on Th cells, and differentiation into CXCR5+ follicular Th cells, all of which are important in the GC reaction. We have therefore taken advantage of ICOS–/– mice to dissect which downstream elements are required to initiate the formation of GC. In the context of a T-dependent immune response, we found that GC B cells from ICOS–/– mice express lower levels of LT
β compared with wild-type GC B cells in vivo, and stimulation of ICOS on T cells induces LTβ on B cells in vitro. Administration of agonistic anti-LTβ receptor Ab was unable to restore the GC response in ICOS–/– mice, suggesting that additional input from another pathway is required for optimal GC generation. In contrast, treatment with agonistic anti-CD40 Ab in vivo recovered GC networks and restored LTβ expression on GC B cells in ICOS–/– mice, and this effect was dependent on LTβ receptor signaling. Collectively, these data demonstrate that ICOS activation is a prerequisite for the up-regulation of LTβ on GC B cells in vivo and provide a model for cooperation between ICOS, CD40, and LT pathways in the context of the GC response.
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1 This work was supported by an operating grant from the Canadian Institutes of Health Research (Grant 165683 to J.L.G.), an Ontario Graduate Studentship award (to F.V.), the National Institutes of Health (Grant R37A133068 to C.F.W.), and Associazione Italiana Ricerca sul Cancro (to U.D.).
2 Address correspondence and reprint requests to Dr. Jennifer L. Gommerman, Department of Immunology, University of Toronto, 1 King’s College Circle, Toronto, Ontario, Canada, M5S 1A8. E-mail address: jen.gommerman{at}utoronto.ca
3 Abbreviations used in this paper: GC, germinal center; AP, alkaline phosphatase; CGG, chicken 
-globulin; FDC, follicular dendritic cell; KLH, keyhole limpet hemocyanin; LT, lymphotoxin; LTβR, lymphotoxin β receptor; MFI, mean fluorescence intensity; NP, (4-hydroxy-3-nitrophenyl)acetyl; PNA, peanut lectin (agglutinin); WT, wild type.
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