CD4+ Th cells resembling regulatory T cells that inhibit chronic colitis differentiate in the absence of interactions between CD4 and class II MHC.
Regulatory CD4+ Th cells can prevent many autoimmune diseases; however, the factors selecting for these cells remain poorly defined. In transgenic mice with a mutation in the CD4 binding region on class II MHC, the disruption of CD4-class II interactions selected for CD4+ Th cells that expressed surface markers and cytokines associated with regulatory Th cells. Th cells from these mice were enriched for CD45RB(low) as well as CD25+, while they expressed high levels of the transcription factor associated with regulatory T cells, Foxp3, and cytokines, including IL-4, IL-10, and IFN-gamma mRNA and protein. These regulatory Th cells inhibited the function of APCs via IL-10 production, and adoptive transfer of these cells prevented weight loss and inflammation in a model of colitis. CD4+ regulatory Th cells emerged only when interactions between CD4 and class II MHC were deficient on cells of nonhemopoietic origin. These data support a novel model controlling the differentiation of regulatory Th cells and suggest that interactions between CD4 and class II MHC may a useful target for re-educating T cells as a treatment for inflammatory diseases.
Denning
Timothy L
TL
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Qi
Hai
H
König
Rolf
R
Scott
Kevin G
KG
Naganuma
Makoto
M
Ernst
Peter B
PB
D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D002908:Chronic Disease; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000276:immunology; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016753:Interleukin-10 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology*; D019282:Wasting Syndrome / Q000235:genetics / Q000276:immunology / Q000517:prevention & control
D015704:CD4 Antigens; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; C474482:I-A(b) antigen, mouse; D016753:Interleukin-10; D007371:Interferon-gamma