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Role of CXCR5 and CCR7 in Follicular Th Cell Positioning and Appearance of a Programmed Cell Death Gene-1^High Germinal Center-Associated Subpopulation¹

Nicole M. Haynes^2,*, Christopher D. C. Allen^*,, Robin Lesley^3,*, K. Mark Ansel^4,*, Nigel Killeen and Jason G. Cyster^5,*,

^* Howard Hughes Medical Institute and Department of Microbiology and Immunology and Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143

Th cell access to primary B cell follicles is dependent on CXCR5. However, whether CXCR5 induction on T cells is sufficient in determining their follicular positioning has been unclear. In this study, we find that transgenic CXCR5 overexpression is not sufficient to promote follicular entry of naive T cells unless the counterbalancing influence of CCR7 ligands is removed. In contrast, the positioning of Ag-engaged T cells at the B/T boundary could occur in the absence of CXCR5. The germinal center (GC) response was 2-fold reduced when T cells lacked CXCR5, although these T cells were able to access the GC. Finally, CXCR5^highCCR7^low T cells were found to have elevated IL-4 transcript and programmed cell death gene-1 (PD-1) expression, and PD-1^high cells were reduced in the absence of T cell CXCR5 or in mice compromised in GC formation. Overall, these findings provide further understanding of how the changes in CXCR5 and CCR7 expression regulate Th cell positioning during Ab responses, and they suggest that development and/or maintenance of a PD-1^high follicular Th cell subset is dependent on appropriate interaction with GC B cells.

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 National Institutes of Health Grant AI45093. N.M.H. was supported by the National Health and Medical Research Council of Australia CJ Martin Fellowship; C.D.C.A. was supported by a Howard Hughes Medical Institute predoctoral fellowship. J.G.C. is an investigator of the Howard Huges Medical Institute.

² Current address: Peter MacCallum Cancer Institute, Research Division, Locked Bag 1, A’Beckett Street, Melbourne, Victoria, Australia, 8006.

³ Current address: Washington University, Microbiology Department, Box 357242, Seattle, WA 98195.

⁴ Current address: Center for Blood Research Institute for Biomedical Research, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115.

⁵ Address correspondence and reprint requests to Dr. Jason G. Cyster, Department of Microbiology and Immunology, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0414. E-mail address: Jason.Cyster{at}ucsf.edu

⁶ Abbreviations used in this paper: GC, germinal center; ASC, Ab-secreting cell; DEL, duck egg lysozyme; FDC, follicular dendritic cell; HEL, hen egg lysozyme; int, intermediate; NP, (4-hydroxy-3-nitrophenyl)acetyl; CGG, chicken -globulin; PD-1, programmed cell death gene-1; SDF-1, stromal cell-derived factor.