Regulation of T cell immunity and tolerance in vivo by CD4.
Previous experiments showed that peptides corresponding to a major CD4-binding site on the beta2 domain of MHC class II molecules, IAbeta134-148, enhance responses by CD4+ T lymphocytes to antigen, allo-antigen and bacterial superantigen in vitro, and to soluble protein in vivo. To determine whether peptide IAbeta134-148 acted by inhibiting antigen-induced T cell tolerance, ovalbumin-specific CD4+ lymph node (LN) T cells from TCR transgenic DO.11.10 mice were adoptively transferred into H-2 syngeneic BALB/c recipients. Tolerance was then induced by injecting antigen i.v. When peptide IAbeta134-148 was used to interfere with CD4-MHC class II interactions, accumulation of clonotype-positive T lymphocytes in the LN and induction of T cell tolerance in vivo were delayed. The mechanism by which peptide IAbeta134-148 inhibited T cell tolerance included the peptide's ability to block activation-induced cell death. Further, antigen-specific splenic T lymphocytes were not tolerized in IAbeta134-148-treated mice, providing a reservoir of T cells that could respond to a secondary immunization. The results reported here suggest that participation of the T cell co-receptor, CD4, in TCR signaling differentially affected both T cell migration and the induction of antigen-specific tolerance. Therefore, in this in vivo model system, the combined strength of all signals received (e.g. via TCR, co-receptors and co-stimulators) determined whether T cell immunity or apoptosis and tolerance resulted from antigenic stimulation. These findings are potentially important for the development of reagents to enhance vaccine efficacy and tumor immunity.
Shen
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X
Department of Microbiology and Immunology and the Sealy Center for Molecular Science, The University of Texas Medical Branch, Galveston 77555-1070, USA.
König
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R
D000818:Animals; D018106:CD28 Antigens / Q000502:physiology; D015704:CD4 Antigens / Q000502:physiology*; D002460:Cell Line; D000949:Histocompatibility Antigens Class II / Q000502:physiology; D007108:Immune Tolerance; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D018106:CD28 Antigens; D015704:CD4 Antigens; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D010047:Ovalbumin