title: CD28 facilitates the generation of Foxp3(-) cytokine responsive regulatory T cell precursors.
abstract: The T cell costimulatory molecule CD28 plays an important role in the thymic generation of Foxp3(+) regulatory T cells (Tregs) essential for the maintenance of self-tolerance. In this study, we show that a cell-intrinsic signal from CD28 is involved in the generation of cytokine-responsive Foxp3(-) precursors using studies of mixed bone marrow chimeras as well as TCR-specific generation of Foxp3(+) cells using intrathymic transfer of TCR-transgenic thymocytes expressing a natural Treg TCR. Contrary to a previous report, the analysis of CD28 mutant knockin mice revealed that this cell-intrinsic signal is only partially dependent on the Lck-binding PYAP motif. Surprisingly, even though the absence of CD28 resulted in a 6-fold decrease in thymic Tregs, the TCR repertoires of CD28-deficient and sufficient cells were largely overlapping. Thus, these data suggest that CD28 does not operate by markedly enlarging the repertoire of TCRs available for Treg development, but rather by improving the efficiency of Treg development of thymocytes expressing natural Treg TCRs.
authors.affiliation: Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Chan-Wang J
authors.initials: CW
authors.lastname: Lio
authors.forename: Lindzy F
authors.initials: LF
authors.lastname: Dodson
authors.forename: Christine M
authors.initials: CM
authors.lastname: Deppong
authors.forename: Chyi-Song
authors.initials: CS
authors.lastname: Hsieh
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Green
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D055879:Gene Knock-In Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D054504:Precursor Cells, T-Lymphoid / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell