title: A B-1a cell subset induces Foxp3(-) T cells with regulatory activity through an IL-10-independent pathway.
abstract: Regulatory T (Treg) cells play a critical role in the maintenance of tolerance. B-1a cells belong to a specific and functionally important B-cell subset that exerts its regulatory role through the production of IL-10. While IL-10 has been correlated with the induction of type 1 Treg (Tr1) cells or Tr1-like cells, whether IL-10-producing B-1a cells are able to induce Treg cells, especially the Tr1 lineage, is poorly understood. We have demonstrated that, similar to the reported B-2 cells, B-1a cells are able to convert naïve CD4(+)CD25(-) T cells into a subset of T cells with suppressive function, which we called 'Treg-of-B1a' cells. Treg-of-B1a cells do not express Foxp3, but upregulate the Treg markers OX40, programmed death 1 (PD-1), inducible costimulator (ICOS) and IL-10R. Moreover, Treg-of-B1a cells do not express Foxp3 and produce high levels of IFN-γ and IL-10, but minimal amounts of IL-4; therefore, they resemble Tr1 cells. However, utilizing IL-10(-/-) mice, we showed that IL-10 was not involved in the induction of Treg-of-B1a cells. On the contrary, CD86-mediated costimulation was essential for B-1a cells to drive the induction of Treg-of-B1a cells. Finally, we demonstrated that, in contrast to the Treg cells generated by B-2 cells that mediate contact-dependent suppression, Treg-of-B1a cells suppress through secreting soluble factors. While Tr1 cells mediate suppression mainly through IL-10 or TGF-β secretion, Treg-of-B1a cells mediate suppression through an IL-10- and TGF-β-independent pathway. Together, these findings suggest that B-1a cells induce a functionally and phenotypically distinct Treg population that is dissimilar to the reported Foxp3(+) Treg or Tr1 cells.
authors.affiliation: Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, China.
authors.forename: Ling-Hui
authors.initials: LH
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, China.
authors.forename: Kun-Po
authors.initials: KP
authors.lastname: Li
authors.affiliation: Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, China.
authors.forename: Kuan-Hua
authors.initials: KH
authors.lastname: Chu
authors.affiliation: 1] Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, China [2] Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan, China.
authors.forename: Bor-Luen
authors.initials: BL
authors.lastname: Chiang
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D060151:B-Lymphocytes, Regulatory / Q000276:immunology*; D002454:Cell Differentiation; D019070:Cell Lineage; D016207:Cytokines / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism; D007365:Intercellular Junctions / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019899:Paracrine Communication; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D016753:Interleukin-10