title: The origin of thymic CD4+CD25+ regulatory T cells and their co-stimulatory requirements are determined after elimination of recirculating peripheral CD4+ cells.
abstract: Studies on the thymic ontogeny of naturally arising CD4(+)CD25(+) regulatory T cells (TR cells) are complicated by the contamination of recirculating cells from the periphery (both activated CD4(+) T and TR cells). We investigated TR cells in anti-CD4 antibody transgenic (Tg) (GK) mice that continuously deplete peripheral CD4 T cells but not thymocytes so that the generation of thymic TR cells and their developmental requirement can be accurately assessed. We show that in the thymuses of mice that lack peripheral CD4(+) cells, TR cells were present but were fewer in number compared with wild-type (WT) mice. Therefore, we show that peripheral TR cells do re-enter the thymus, comprising 20% of TR cells in the normal thymus. TR cells from both WT and GK mice expressed Foxp3 and GITR, and suppressed the proliferation of CD25(-)CD4(+) T cells. Furthermore, the co-stimulation requirements for TR generation were evaluated in mice with or without peripheral CD4 cells. Splenic TR cells in CD40L(-/-) mice and CTLA4Ig Tg mice were fewer compared with WT mice. Mice deficient in both co-stimulatory pathways had further reduction in splenic TR cells. Unlike the periphery, the reduction in thymic TR cells was only seen for CD40L(-/-) but not for CTLA4Ig Tg mice. Therefore, we found that the co-stimulation requirements for the thymic development of TR cells differed from those for peripheral homeostasis.
authors.affiliation: Autoimmunity and Transplantation Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. zhan@wehi.edu.au
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhan
authors.forename: Dorothee
authors.initials: D
authors.lastname: Bourges
authors.forename: James A
authors.initials: JA
authors.lastname: Dromey
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Harrison
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lew
mesh_terms: D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics; D018106:CD28 Antigens / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology; D002452:Cell Count; D002454:Cell Differentiation / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D018920:Coculture Techniques; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D053450:Glucocorticoid-Induced TNFR-Related Protein; D018796:Immunoconjugates / Q000235:genetics / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017475:Receptors, Nerve Growth Factor / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; D018796:Immunoconjugates; D053645:Interleukin-2 Receptor alpha Subunit; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; D023201:CD40 Ligand; D000069594:Abatacept