Follicular B Helper T Cells Express Cxc Chemokine Receptor 5, Localize to B Cell Follicles, and Support Immunoglobulin Production

By D. Breitfeld, L. Ohl, E. Kremmer, J. Ellwart, F. Sallusto, M. Lipp, R. Förster. Journal of Experimental Medicine, 2000

1,533 citations recorded by the source corpus.

Chemokines and their receptors have been identified as major regulators controlling the functional 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, CD4+CXCR5+ 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 inducible costimulator (ICOS), a recently identified costimulatory molecule of the CD28 family. Thus, when compared with CD4+CD45RO+CXCR5− cells, CD4+CD45RO+CXCR5+ tonsillar T cells efficiently support the production of immunoglobulin (Ig)A and IgG. In contrast, analysis of the memory response revealed that long-lasting memory cells are found within the CD4+CD45RO+CXCR5− population, suggesting that CXCR5+CD4 cells represent recently activated effector cells. Based on the characteristic localization within secondary lymphoid organs, we suggest to term these cells “follicular B helper T cells” (TFH).

Subfields: Immunology

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In Immunology

1. Shane Crotty
2. W. E. Paul
3. Jinfang Zhu
4. A. Jetten
5. J. Cyster
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7. C. Mackay
8. Jacques Banchereau

Citations in the corpus

• Inflammatory and immune pathways in the pathogenesis of periodontal disease (2014, background): “expression of the chemokine receptor, chemokine (C-X-C motif) receptor 5 (24, 50, 211).”
• Generation of follicular helper T cells is mediated by IL-21 but independent of TH1, TH2 or TH17 lineages (2008, background): “ICOS was previously shown to be expressed at high levels on human tonsillular CXCR5 T cells within the light zone of germinal centers and efficiently supported the immunoglobulin production (Breitfeld et al., 2000; Schaerli et al., 2000).”
• Differentiation of Effector CD4 T Cell Populations (2010, positive): “Bcl-6 is also expressed in Tfh cells (98) as is CXCR5, a critical chemokine receptor that allows cells to home to B cell follicles (99).”
• T follicular helper (TFH) cells in normal and dysregulated immune responses. (2008, background): “However, expression of Bcl-6 by T cells in follicles is by no means uniform: Only 10%–15% of CD4+ T cells in GCs appear to express Bcl-6 protein (65).”
• Subspecialization of Cxcr5+ T Cells (2001, positive): “In line with this, it has been recently reported that CXCR5 defines Th cells with B cell helper function (32, 33).”
• Multiple layers of B cell memory with different effector functions (2009, background): “These FDC-associated B cells were also in close contact with CD4 + T cells that could correspond to the population of long-lived memory follicular helper T cell”
• Follicular helper T cells serve as the major CD4 T cell compartment for HIV-1 infection, replication, and production (2013, background): “…et al., 2009) is the primary marker of Tfh cells, whereas other markers, such as CXCR5 (the chemokine receptor for CXCL13), inducible T cell co-stimulator (ICOS), and PD-1 (Breitfeld et al., 2000; Schaerli et al., 2000; Kim et al., 2001; Fazilleau et al., 2009a), are not exclusive of Tfh cells.”
• The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms (2022, background): “Nodal T-follicular helper cell lymphomas: New nomenclature to unite family members This family includes three entities of nodal T-cell lymphomas that bear the phenotype and gene expression signatures of T-follicular helper (TFH) cells [262, 263].”
• CD4⁺ follicular helper T cell infiltration predicts breast cancer survival. (2013, neutral): “Tfh cells are relative newcomers to the Th subset family (71, 72) and have not been previously described in nonhematological tumors.”
• The chemokine and chemokine receptor superfamilies and their molecular evolution (2006, background): “Another example is the CXCL13-CXCR5 pair, which is pivotal for successful B cell homing and, because it regulates T cell-B cell interactions, for the production of antibodies [18].”
• Human Blood CXCR5+CD4+ T Cells Are Counterparts of T Follicular Cells and Contain Specific Subsets that Differentially Support Antibody Secretion (2011, background): “Immunity 34, 108–121, January 28, 2011 ª2011 Elsevier Inc. 111 (A) IL-21 secretion by blood Th cell subsets cultured with naive B cells.”
• Human Circulating PD-1+CXCR3−CXCR5+ Memory Tfh Cells Are Highly Functional and Correlate with Broadly Neutralizing HIV Antibody Responses (2013, neutral): “Whereas TEM cells lack CCR7 and migrate to inflamed tissues, TCM cells ex- press CCR7 and circulate through secondary lymphoid organs.”