Abstract
The majority of CXCR5(+) PD1(+) CD4(+) T follicular helper (Tfh) cells (>90%) are CD25(-) Bcl6(hi) , while a small subpopulation (<10%) are CD25(+) Bcl6(low) but do not express FoxP3 and are not T regulatory cells. We purified T:B-cell conjugates from tonsils and found they were enriched for the CD25(+) Bcl6(low) Tfh-cell subpopulation. In response to IL-2, these CD25(+) Tfh cells increased expression of costimulatory molecules ICOS or OX40, upregulated transcription factor cMaf, produced cytokines IL-21, IL-17, and IL-10, and raised the levels of antiapoptotic protein Bcl2. Conjugates formed with CD25(+) BCl6(low) Tfh cells included B cells expressing higher levels of activation-induced cytidine deaminase (AID), memory marker CD45RO, surface IgG or IgA, and MHC class II compared to B-cell conjugates including CD25(-) Bcl6(hi) Tfh cells. While IL-2 suppresses early Tfh-cell differentiation, Tfh-cell recognition of antigen-presenting B cells and signaling through the T-cell receptor likely triggers expression of the high-affinity IL-2 receptor and responses to IL-2 including downregulation of Bcl6. CD25 expression on Tfh cells and local production of IL-2 in tonsil or lymph node may support B helper T-cell function during later stages of B-cell maturation and the development of immune memory.
Keywords:
B cells; Germinal centers; IL-2 receptor; Interleukin-2; T follicular helper cell.
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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B-Lymphocytes / cytology*
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B-Lymphocytes / drug effects
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B-Lymphocytes / immunology
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Cell Differentiation
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Cytidine Deaminase / genetics
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Cytidine Deaminase / immunology
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Cytokines / genetics
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Cytokines / immunology
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / immunology
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Gene Expression Regulation
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Germinal Center / cytology*
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Germinal Center / drug effects
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Germinal Center / immunology
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Humans
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Immunologic Memory
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Inducible T-Cell Co-Stimulator Protein / genetics
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Inducible T-Cell Co-Stimulator Protein / immunology
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Interleukin-2 / pharmacology
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Leukocyte Common Antigens / genetics
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Leukocyte Common Antigens / immunology
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Lymphocyte Activation / drug effects
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Palatine Tonsil / cytology*
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Palatine Tonsil / drug effects
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Palatine Tonsil / immunology
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Proto-Oncogene Proteins c-bcl-6
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Proto-Oncogene Proteins c-maf / genetics
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Proto-Oncogene Proteins c-maf / immunology
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Receptors, Interleukin-2 / genetics*
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Receptors, Interleukin-2 / immunology
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Receptors, OX40 / genetics
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Receptors, OX40 / immunology
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Signal Transduction
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T-Lymphocytes, Helper-Inducer / cytology*
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T-Lymphocytes, Helper-Inducer / drug effects
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T-Lymphocytes, Helper-Inducer / immunology
Substances
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BCL6 protein, human
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Cytokines
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DNA-Binding Proteins
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ICOS protein, human
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Inducible T-Cell Co-Stimulator Protein
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Interleukin-2
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Proto-Oncogene Proteins c-bcl-6
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Proto-Oncogene Proteins c-maf
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Receptors, Interleukin-2
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Receptors, OX40
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TNFRSF4 protein, human
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Leukocyte Common Antigens
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AICDA (activation-induced cytidine deaminase)
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Cytidine Deaminase