CD25(+) Bcl6(low) T follicular helper cells provide help to maturing B cells in germinal centers of human tonsil

Eur J Immunol. 2015 Jan;45(1):298-308. doi: 10.1002/eji.201444911. Epub 2014 Oct 27.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / cytology*
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • Cell Differentiation
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / immunology
  • Cytokines / genetics
  • Cytokines / immunology
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / immunology
  • Gene Expression Regulation
  • Germinal Center / cytology*
  • Germinal Center / drug effects
  • Germinal Center / immunology
  • Humans
  • Immunologic Memory
  • Inducible T-Cell Co-Stimulator Protein / genetics
  • Inducible T-Cell Co-Stimulator Protein / immunology
  • Interleukin-2 / pharmacology
  • Leukocyte Common Antigens / genetics
  • Leukocyte Common Antigens / immunology
  • Lymphocyte Activation / drug effects
  • Palatine Tonsil / cytology*
  • Palatine Tonsil / drug effects
  • Palatine Tonsil / immunology
  • Proto-Oncogene Proteins c-bcl-6
  • Proto-Oncogene Proteins c-maf / genetics
  • Proto-Oncogene Proteins c-maf / immunology
  • Receptors, Interleukin-2 / genetics*
  • Receptors, Interleukin-2 / immunology
  • Receptors, OX40 / genetics
  • Receptors, OX40 / immunology
  • Signal Transduction
  • T-Lymphocytes, Helper-Inducer / cytology*
  • T-Lymphocytes, Helper-Inducer / drug effects
  • T-Lymphocytes, Helper-Inducer / immunology

Substances

  • BCL6 protein, human
  • Cytokines
  • DNA-Binding Proteins
  • ICOS protein, human
  • Inducible T-Cell Co-Stimulator Protein
  • Interleukin-2
  • Proto-Oncogene Proteins c-bcl-6
  • Proto-Oncogene Proteins c-maf
  • Receptors, Interleukin-2
  • Receptors, OX40
  • TNFRSF4 protein, human
  • Leukocyte Common Antigens
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase