title: Regulated costimulation in the thymus is critical for T cell development: dysregulated CD28 costimulation can bypass the pre-TCR checkpoint.
abstract: Expression of CD28 is highly regulated during thymic development, with CD28 levels extremely low on immature thymocytes but increasing dramatically as CD4- CD8- cells initiate expression of TCRbeta. B7-1 and B7-2, the ligands for CD28, have a restricted distribution in the thymic cortex where immature thymocytes reside and are more highly expressed in the medulla where the most mature thymocytes are located. To determine the importance of this regulated CD28/B7 expression for T cell development, we examined the effect of induced CD28 signaling of immature thymocytes in CD28/B7-2 double-transgenic mice. Strikingly, we found that differentiation to the CD4+ CD8+ stage in CD28/B7-2 transgenics proceeds independent of the requirement for TCRbeta expression manifest in wild-type thymocytes, occurring even in Rag- or CD3epsilon- knockouts. These findings indicate that signaling of immature thymocytes through CD28 in the absence of TCR- or pre-TCR-derived signals can promote an aberrant pathway of T cell differentiation and highlight the importance of finely regulated physiologic expression of CD28 and B7 in maintaining integrity of the "beta" checkpoint for pre-TCR/TCR-dependent thymic differentiation.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Joy A
authors.initials: JA
authors.lastname: Williams
authors.forename: Karen S
authors.initials: KS
authors.lastname: Hathcock
authors.forename: David
authors.initials: D
authors.lastname: Klug
authors.forename: Yohsuke
authors.initials: Y
authors.lastname: Harada
authors.forename: Baishakhi
authors.initials: B
authors.lastname: Choudhury
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.forename: Ryo
authors.initials: R
authors.lastname: Abe
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hodes
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D017252:CD3 Complex / Q000235:genetics; D002454:Cell Differentiation / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000187:drug effects / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C499311:RAG2 protein, human; D016693:Receptors, Antigen, T-Cell, alpha-beta