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Foxp3+ follicular regulatory T cells control the germinal center response

Nat Med. 2011 Jul 24;17(8):975-82. doi: 10.1038/nm.2425.

Abstract

Follicular helper (T(FH)) cells provide crucial signals to germinal center B cells undergoing somatic hypermutation and selection that results in affinity maturation. Tight control of T(FH) numbers maintains self tolerance. We describe a population of Foxp3(+)Blimp-1(+)CD4(+) T cells constituting 10-25% of the CXCR5(high)PD-1(high)CD4(+) T cells found in the germinal center after immunization with protein antigens. These follicular regulatory T (T(FR)) cells share phenotypic characteristics with T(FH) and conventional Foxp3(+) regulatory T (T(reg)) cells yet are distinct from both. Similar to T(FH) cells, T(FR) cell development depends on Bcl-6, SLAM-associated protein (SAP), CD28 and B cells; however, T(FR) cells originate from thymic-derived Foxp3(+) precursors, not naive or T(FH) cells. T(FR) cells are suppressive in vitro and limit T(FH) cell and germinal center B cell numbers in vivo. In the absence of T(FR) cells, an outgrowth of non-antigen-specific B cells in germinal centers leads to fewer antigen-specific cells. Thus, the T(FH) differentiation pathway is co-opted by T(reg) cells to control the germinal center response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism*
  • Cell Differentiation / immunology*
  • DNA-Binding Proteins / genetics
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Forkhead Transcription Factors / metabolism*
  • Germinal Center / immunology*
  • Humans
  • Immunohistochemistry
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Positive Regulatory Domain I-Binding Factor 1
  • Proto-Oncogene Proteins c-bcl-6
  • Receptors, CXCR5 / metabolism
  • Repressor Proteins / metabolism
  • Self Tolerance / immunology*
  • Statistics, Nonparametric
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • T-Lymphocytes, Regulatory / physiology

Substances

  • Bcl6 protein, mouse
  • CXCR5 protein, human
  • DNA-Binding Proteins
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Membrane Proteins
  • Proto-Oncogene Proteins c-bcl-6
  • Receptors, CXCR5
  • Repressor Proteins
  • PRDM1 protein, human
  • Positive Regulatory Domain I-Binding Factor 1