title: Cbl-b(-/-) T cells demonstrate in vivo resistance to regulatory T cells but a context-dependent resistance to TGF-beta.
abstract: Cbl-b is an E3 ubiquitin ligase that negatively regulates T cell activation. Cbl-b(-/-) mice develop spontaneous autoimmunity, and Cbl-b dysregulation has been described in both murine and human autoimmune diseases. Although the mechanisms underlying the development of autoimmunity in Cbl-b(-/-) mice are not yet clear, we have reported that Cbl-b(-/-) CD4(+)CD25(-) effector T cells (Teffs) are resistant to CD4(+)CD25(+) regulatory T cell (Treg)-mediated suppression in vitro and have suggested that this may be an important mechanism in the development of autoimmunity. To confirm the relevance of this resistance to autoimmune disease, we now show that Cbl-b(-/-) Teffs are resistant to suppression by Tregs in vivo and that this involves a resistance of truly naive Cbl-b(-/-) Teffs. Additionally, we show that Cbl-b(-/-) Tregs are fully functional in vivo, further suggesting that the regulatory abnormalities in Cbl-b(-/-) mice are related to defects in Teff, not Treg, function. To characterize the relevance of TGF-beta sensitivity in Treg resistance, we examined in vivo Th17 generation and report that Cbl-b(-/-) mice are able to mount a normal Th17 response in vivo. As Cbl-b(-/-) Teffs have been shown to be insensitive to the suppressive effects of TGF-beta in other in vivo models, the present results suggest that Cbl-b(-/-) Teffs demonstrate a context-dependent sensitivity to TGF-beta in vivo. Overall, our results suggest that resistance to Tregs may be a bona fide mechanism underlying autoimmunity and that Cbl-b(-/-) mice offer unique approaches for studying the interrelationships between Treg function, TGF-beta-mediated responses, and the development of autoimmunity.
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06032, USA.
authors.forename: Catherine O
authors.initials: CO
authors.lastname: Adams
authors.forename: William J
authors.initials: WJ
authors.lastname: Housley
authors.forename: Sourojit
authors.initials: S
authors.lastname: Bhowmick
authors.forename: Robert E
authors.initials: RE
authors.lastname: Cone
authors.forename: Thiruchandurai V
authors.initials: TV
authors.lastname: Rajan
authors.forename: Faripour
authors.initials: F
authors.lastname: Forouhar
authors.forename: Robert B
authors.initials: RB
authors.lastname: Clark
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000906:Antibodies; D020381:Interleukin-17; D016212:Transforming Growth Factor beta; D018664:Interleukin-12; D007371:Interferon-gamma; D050721:Proto-Oncogene Proteins c-cbl