Follicular B Helper T Cells Express CXC Chemokine Receptor 5, Localize to B Cell Follicles, and Support Immunoglobulin Production By Dagmar Breitfeld,* Lars Ohl,* Elisabeth Kremmer,‡ Joachim Ellwart,‡ Federica Sallusto,§ Martin Lipp,* and Reinhold Förster* From *Molecular Tumor and Immunogenetics, Max-Delbrück Center for Molecular Medicine, 13092 Berlin, Germany; the ‡Institute of Molecular Immunology, GSF National Research Center for Environment and Health, 81377 München, Germany; and the §Institute of Research in Biomedicine, 6500 Belinzona, Switzerland Abstract Chemokines and their receptors have been identified as major regulators controlling the func- tional organization of secondary lymphoid organs. Here we show that expression of CXC chemokine receptor 5 (CXCR5), a chemokine receptor required for B cell homing to B cell follicles, defines a novel subpopulation of B helper T cells localizing to follicles. In peripheral blood these cells coexpress CD45RO and the T cell homing CC chemokine receptor 7 (CCR7). In secondary lymphoid organs, CD41CXCR51 cells lose expression of CCR7, which allows them to localize to B cell follicles and germinal centers where they express high levels of CD40 ligand (CD40L), a costimulatory molecule required for B cell activation and in- ducible costimulator (ICOS), a recently identified costimulatory molecule of the CD28 family. Thus, when compared with CD41CD45RO1CXCR52 cells, CD41CD45RO1CXCR51 tonsillar T cells efficiently support the production of immunoglobulin (Ig)A and IgG. In con- trast, analysis of the memory response revealed that long-lasting memory cells are found within the CD41CD45RO1CXCR52 population, suggesting that CXCR51CD4 cells represent re- cently activated effector cells. Based on the characteristic localization within secondary lym- phoid organs, we suggest to term these cells “follicular B helper T cells” (TFH). Key words: CXC chemokine receptor 5 • CC chemokine receptor 7 • T cell homing • germinal centers • T helper cells Introduction To efficiently combat invading pathogens, lymphocytes continuously circulate through lymphoid and nonlym- phoid tissue to mount an adaptive immune response. Lym- phocyte trafficking does not occur at random, but is sub- jected to tightly controlled mechanisms allowing selective entry of lymphocytes into secondary lymphoid organs and into functional compartments within these organs (1). Recent data provide strong experimental evidence that chemokines and their receptors are mandatory for the ho- meostatic regulation of lymphocyte trafficking and func- tional compartmentalization of lymphoid organs (2). The majority of B and T lymphocytes have to interact with Address correspondence to Reinhold Förster, Max-Delbrück Center for Molecular Medicine, Robert-Rössle Str. 10, D-13092 Berlin, Germany. Phone: 49-30-9406-3330; Fax: 49-30-9406-3884; E-mail: rfoerst@ mdc-berlin.de specialized high endothelial venules (HEVs)1 and pass through them in order to enter lymphoid organs. We recently demonstrated that CC chemokine receptor 7 (CCR7) is indispensable for the migration of naive T cells through these venules. In addition, B cells exploit CCR7 to efficiently enter LNs and Peyer’s patches (3). Once B cells are within lymphoid organs, they use CXC chemo- kine receptor 5 (CXCR5 [4]) to follow a follicular chemo- kine gradient of B lymphocyte chemoattractant (BLC [5]), which guides them to the B cell–rich follicles. BLC is a ligand for CXCR5 which, according to a new classifica- 1Abbreviations used in this paper: BLC, B lymphocyte chemoattractant; CCR7, CC chemokine receptor 7; CXCR5, CXC chemokine receptor 5; DC, dendritic cell; ELC, EBV-induced molecule 1 ligand chemokine; FDC, follicular DC; GC, germinal center; HEV, high endothelial venule; ICOS, inducible costimulator; LT, lymphotoxin; SLC, secondary lym- phoid tissue chemokine; TCM, central memory T cells; TT, tetanus toxin. 1545 J. Exp. Med. The Rockefeller University Press • 0022-1007/2000/12/1545/07 $5.00 Volume 192, Number 11, December 4, 2000 1545–1551 http://www.jem.org/cgi/content/full/192/11/1545