title: Human tonsil B-cell lymphoma 6 (BCL6)-expressing CD4+ T-cell subset specialized for B-cell help outside germinal centers.
abstract: T follicular helper (Tfh) cells represent a Th subset engaged in the help of B-cell responses in germinal centers (GCs). Tfh cells abundantly express the transcription repressor B-cell lymphoma 6 (Bcl6), a factor that is necessary and sufficient for their development in vivo. Whether Tfh or Tfh-committed cells are involved in the help of B cells outside GCs remains unclear, particularly in humans. In this study, we identified a previously undefined BCL6-expressing CD4(+) T-cell subset in human tonsils. This subset expressed IL-7 receptor and chemokine receptor 5 (CXCR5) and inducible costimulator (ICOS) at low levels (CXCR5(lo)ICOS(lo)), and it was found exclusively outside GCs. CXCR5(lo)ICOS(lo) CD4(+) T cells secreted larger amounts of IL-21 and IL-10 than CXCR5(hi)ICOS(hi) GC-Tfh cells upon activation, and they induced proliferation and differentiation of naïve B cells into Ig-producing cells more efficiently than GC-Tfh cells. However, this subset lacked the capacity to help GC-B cells because of the induction of apoptosis of GC-B cells through the FAS/FAS-ligand interaction. CXCR5(lo)ICOS(lo) CD4(+) T cells expressed equivalent amounts of BCL6 transcript with CXCR5(hi)ICOS(hi) GC-Tfh cells, but they expressed less Bcl6 protein. Collectively, our study indicates that CXCR5(lo)ICOS(lo) CD4(+) T cells in human tonsils represent Tfh lineage-committed cells that provide help to naïve and memory B cells outside GCs.
authors.affiliation: Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 75204, USA.
authors.forename: Salah-Eddine
authors.initials: SE
authors.lastname: Bentebibel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Schmitt
authors.forename: Jacques
authors.initials: J
authors.lastname: Banchereau
authors.forename: Hideki
authors.initials: H
authors.lastname: Ueno
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology*; D019070:Cell Lineage / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics; D018858:Germinal Center / Q000276:immunology*; D006801:Humans; D015851:Interleukin-7; D016393:Lymphoma, B-Cell / Q000473:pathology*; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology*; D014067:Tonsillar Neoplasms / Q000473:pathology*
chemical_list: C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D015851:Interleukin-7; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger