title: CXCR5 expressing human central memory CD4 T cells and their relevance for humoral immune responses.
abstract: High expression of CXCR5 is one of the defining hallmarks of T follicular helper cells (T(FH)), a CD4 Th cell subset that promotes germinal center reactions and the selection and affinity maturation of B cells. CXCR5 is also expressed on 20-25% of peripheral blood human central memory CD4 T cells (T(CM)), although the definitive function of these cells is not fully understood. The constitutive expression of CXCR5 on T(FH) cells and a fraction of circulating T(CM) suggests that CXCR5(+) T(CM) may represent a specialized subset of memory-type T(FH) cells programmed for homing to follicles and providing B cell help. To verify this assumption, we analyzed this cell population and show its specialized function in supporting humoral immune responses. Compared with their CXCR5(-) T(CM) counterparts, CXCR5(+) T(CM) expressed high levels of the chemokine CXCL13 and efficiently induced plasma cell differentiation and Ig secretion. We found that the distinct B cell helper qualities of CXCR5(+) T(CM) were mainly due to high ICOS expression and pronounced responsiveness to ICOS ligand costimulation together with large IL-10 secretion. Furthermore, B cell helper attributes of CXCR5(+) T(CM) were almost exclusively acquired on cognate interaction with B cells, but not with dendritic cells. This implies that a preferential recruitment of circulating CXCR5(+) T(CM) to CXCL13-rich B cell follicles is required for the promotion of a quick and efficient protective secondary humoral immune response. Taken together, we propose that CXCR5(+) T(CM) represent a distinct memory cell subset specialized in supporting Ab-mediated immune responses.
authors.affiliation: Immunology Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales 2010, Australia. n.chevalier@garvan.org.au
authors.forename: Nina
authors.initials: N
authors.lastname: Chevalier
authors.forename: David
authors.initials: D
authors.lastname: Jarrossay
authors.forename: Edwin
authors.initials: E
authors.lastname: Ho
authors.forename: Danielle T
authors.initials: DT
authors.lastname: Avery
authors.forename: Cindy S
authors.initials: CS
authors.lastname: Ma
authors.forename: Di
authors.initials: D
authors.lastname: Yu
authors.forename: Federica
authors.initials: F
authors.lastname: Sallusto
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
authors.forename: Charles R
authors.initials: CR
authors.lastname: Mackay
mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D054382:Chemokine CXCL13 / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D056724:Immunity, Humoral; D007156:Immunologic Memory; D060889:Inducible T-Cell Co-Stimulator Protein; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D046228:Microarray Analysis; D014066:Palatine Tonsil / Q000276:immunology; D016133:Polymerase Chain Reaction; D054380:Receptors, CXCR5 / Q000235:genetics* / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; C095085:CXCR5 protein, human; D054382:Chemokine CXCL13; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D054380:Receptors, CXCR5; D016753:Interleukin-10