title: A role for intrathymic B cells in the generation of natural regulatory T cells.
abstract: B cells inhabit the normal human thymus, suggesting a role in T cell selection. In this study, we report that B cells can modulate thymic production of CD4+ Foxp3+ T cells (regulatory T cells [Tregs]). Mice with transgenic expression of BAFF (BAFF-Tg) harbor increased numbers of Helios+ Foxp3+ thymic Tregs and, similar to some human autoimmune conditions, also exhibit increased numbers of B cells colonizing the thymus. Distinct intrathymic B cell subpopulations were identified, namely B220+, IgM+, CD23(hi), CD21(int) cells; B220+, IgM+, CD23(lo), CD21(lo) cells; and a population of B220+, IgM+, CD23(lo), CD21(hi) cells. Anatomically, CD19+ B cells accumulated in the thymic medulla region juxtaposed to Foxp3+ T cells. These intrathymic B cells engender Tregs. Indeed, thymic Treg development was diminished in both B cell-deficient BAFF-Tg chimeras, but also B cell-deficient wild-type chimeras. B cell Ag capture and presentation are critical in vivo events for Treg development. In the absence of B cell surface MHC class II expression, thymic expansion of BAFF-Tg Tregs was lost. Further to this, expansion of Tregs did not occur in BAFF-Tg/Ig hen egg lysozyme BCR chimeras, demonstrating a requirement for Ag specificity. Thus, we present a mechanism whereby intrathymic B cells, through the provision of cognate help, contribute to the shaping of the Treg repertoire.
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2010, Australia; and.
authors.forename: Stacey N
authors.initials: SN
authors.lastname: Walters
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2010, Australia; and.
authors.forename: Kylie E
authors.initials: KE
authors.lastname: Webster
authors.affiliation: College of Medicine, Biology and Environment, Australian National University, Canberra, Australian Capital Territory 0200, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Daley
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2010, Australia; and s.grey@garvan.org.au.
authors.forename: Shane T
authors.initials: ST
authors.lastname: Grey
mesh_terms: D000818:Animals; D000941:Antigens / Q000235:genetics / Q000276:immunology; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology; D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*
chemical_list: D000941:Antigens; D000943:Antigens, Differentiation; D053264:B-Cell Activating Factor; D000949:Histocompatibility Antigens Class II; D011947:Receptors, Antigen, B-Cell; C505720:Tnfsf13b protein, mouse