Resistance to CD4+CD25+ regulatory T cells and TGF-beta in Cbl-b-/- mice.
Cbl-b(-/-) mice have signaling defects that result in CD28-independent T cell activation, increased IL-2 production, hyper-reactive T cells, and increased autoimmunity. Although the increased autoimmunity in these mice is believed to result from the hyper-reactive T cells, the mechanisms leading from T cell hyper-reactivity to autoimmunity remain unclear. Specifically, the function and interaction of CD4(+)CD25(+) regulatory T cells (T(reg)) and CD4(+)CD25(-) effector T cells (T(eff)) in Cbl-b(-/-) mice have not been examined. We now report that Cbl-b(-/-) CD4(+)CD25(+) T(reg) exhibit normal regulatory function in vitro. In contrast, the in vitro response of Cbl-b(-/-) CD4(+)CD25(-) T(eff) is abnormal, in that it is not inhibited by either Cbl-b(-/-) or wild-type T(reg). This resistance of Cbl-b(-/-) T(eff) to in vitro regulation is seen at the levels of both DNA synthesis and cell division. In addition to this resistance to CD4(+)CD25(+) T(reg), Cbl-b(-/-) T(eff) demonstrate in vitro resistance to inhibition by TGF-beta. This second form of resistance in Cbl-b(-/-) T(eff) is seen despite the expression of normal levels of type II TGF-beta receptors and normal levels of phosphorylated Smad3 after TGF-beta stimulation. Coupled with recent reports of resistance to T(reg) in T(eff) exposed to LPS-treated dendritic cells, our present findings suggest that resistance to regulation may be a relevant mechanism in both normal immune function and autoimmunity.
Wohlfert
Elizabeth A
EA
Department of Medicine, Division of Rheumatic Diseases, and Center of Immunotherapy for Cancer and Infectious Diseases, University of Connecticut Health Center, Farmington, CT 06030, USA.
Callahan
Margaret K
MK
Clark
Robert B
RB
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D018920:Coculture Techniques; D051379:Mice; D050721:Proto-Oncogene Proteins c-cbl; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D015704:CD4 Antigens; C118387:Cblb protein, mouse; D015375:Receptors, Interleukin-2; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases