Foxp3+ follicular regulatory T cells control the germinal center response

• DOI: 10.1038/nm.2425
• Publication Date: 2011-07-24T18:17:14Z
• Authors: Michelle A Linterman; Wim Pierson; Sau K Lee; Axel Kallies; Shimpei Kawamoto; Tim F Rayner; Monika Srivastava; Devina P Divekar; Laura Beaton; Jennifer J Hogan; Sidonia Fagarasan; Adrian Liston; Kenneth G C Smith; Carola G Vinuesa
• Keywords: T-Lymphocytes; animal cell; Inbred C57BL; Mice; 0302 clinical medicine; Receptors; signaling lymphocyte activation molecule associated protein; Mice, Knockout; B-Lymphocytes; Statistics; article; Cell Differentiation; Forkhead Transcription Factors; Flow Cytometry; Forkhead Transcription Factors/*metabolism; Immunohistochemistry; DNA-Binding Proteins; Self Tolerance; B-Lymphocytes/*metabolism; Proto-Oncogene Proteins c-bcl-6; Keywords: B lymphocyte induced maturation protein 1; Self Tolerance/*immunology; Receptors, CXCR5; Knockout; animal experiment; transcription factor FOXP3; 610; Enzyme-Linked Immunosorbent Assay; protein bcl 6; Statistics, Nonparametric; animal tissue; 03 medical and health sciences; Animals; Humans; Nonparametric; Germinal Center/*immunology; chemokine receptor CXCR5; Repressor Proteins/metabolism; animal model; Membrane Proteins; Germinal Center; Cell Differentiation/*immunology; Mice, Inbred C57BL; Repressor Proteins; Regulatory/*immunology/metabolism/physiology; CD28 antigen; Membrane Proteins/metabolism; Positive Regulatory Domain I-Binding Factor 1; CXCR5/metabolism; DNA-Binding Proteins/genetics

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.