Germinal centers regulate human Th2 development.
In the present study we demonstrate that all CD4(+) T cells in human tonsil expressing the Th2-selective receptor chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) also 1) express high levels of CXCR5, and 2) display a transitional CD45RA/RO phenotype and consistently do not produce significant amounts of cytokines when immediately analyzed ex vivo. Hence, they represent precursors of Th2 effector cells, a conclusion confirmed by their robust production of IL-4, IL-5, and IL-13, but not IFN-gamma, after in vitro activation. CD4(+) T cells, which express only intermediate levels of CXCR5, instead develop into IFN-gamma-producing cells under identical culture conditions, thus establishing a correlation between relative levels of CXCR5 expression and the acquired cytokine profile. Because CXCR5 is critically involved in follicular localization, the results suggest that these CRTH2(+) Th2 cells preferentially develop their cytokine-producing phenotype within germinal centers (GCs), whereas extrafollicular differentiation instead promotes Th1 development. In support for this proposal, we show that T cells with an intermediate expression of CXCR5 can be forced to also produce IL-4 and IL-13 if cultured with allogenic GC B cells. Finally, we demonstrate that the previously described CD57(+) GC T cells also express high levels of CXCR5 but instead of comprising a Th2 precursor, they represent anergized T cells. Taken together, these data suggest that GCs and B cells regulate CD4(+) T cell differentiation in a finely tuned fashion, either by promoting differentiation of Th2 cells, which apparently leave the lymphoid tissue before evolving a cytokine-producing phenotype, or by furnishing T cell unresponsiveness.
Johansson-Lindbom
Bengt
B
Department of Immunotechnology, Lund University, Lund, Sweden.
Ingvarsson
Sigurdur
S
Borrebaeck
Carl A K
CA
D016175:B-Lymphocyte Subsets / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018959:CD57 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D019743:Chemokines, CXC / Q000378:metabolism; D002648:Child; D017635:Clonal Anergy; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D018858:Germinal Center / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D018793:Interleukin-13 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D014066:Palatine Tonsil; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000096:biosynthesis; D011971:Receptors, Immunologic / Q000096:biosynthesis; D011982:Receptors, Prostaglandin; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism
D018959:CD57 Antigens; C095085:CXCR5 protein, human; D019743:Chemokines, CXC; D016207:Cytokines; D018793:Interleukin-13; D011948:Receptors, Antigen, T-Cell; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D015847:Interleukin-4; D007371:Interferon-gamma; C036293:prostaglandin D2 receptor