Acquired pMHC I complexes greatly enhance CD4(+) Th cell's stimulatory effect on CD8(+) T cell-mediated diabetes in transgenic RIP-mOVA mice.
CD4(+) helper T (Th) cells play pivotal roles in induction of CD8(+) CTL immunity. However, the mechanism of CD4(+) T cell help delivery to CD8(+) T cells in vivo is still elusive. In this study, we used ovalbumin (OVA)-pulsed dendritic cells (DC(OVA)) to activate OT-II mouse CD4(+) T cells, and then studied the help effect of these CD4(+) T cells on CD8(+) cytotoxic T lymphocyte (CTL) responses. We also examined CTL mediated islet beta cell destruction which led to diabetes in wild-type C57BL/6 mice and transgenic rat insulin promoter (RIP)-mOVA mice expressing beta cell antigen OVA with self OVA-specific tolerance, respectively. In adoptive transfer experiments, we demonstrated that help, in the form of peptide/major histocompatibility complex (pMHC) I acquired from DC(OVA) by DC(OVA) activation, was required for induction of OVA-specific CTL responses in C57BL/6 mice. However, in combination with TCR transgenic OT-I mouse CD8(+) T cells, the tolerogenic dosage of CD4(+) Th cells with acquired pMHC I, but not CD4(+) K(b-/-) Th cells without acquired pMHC I were able to cause diabetes in 8/10 (80%) RIP-mOVA mice. This study thus expands the current knowledge in T cell-mediated autoimmunity and provides insight into the nature of CD4(+) T cell-mediated help in CD8(+) CTL induction.
Ahmed
Khawaja Ashfaque
KA
Research Unit, Saskatchewan Cancer Agency, Department of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, Canada.
Xie
Yufeng
Y
Zhang
Xueshu
X
Xiang
Jim
J
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology; D003920:Diabetes Mellitus / Q000276:immunology* / Q000473:pathology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007328:Insulin / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D010455:Peptides / Q000276:immunology*; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics*; D051381:Rats; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D015395:Histocompatibility Antigens Class I; D007328:Insulin; D010455:Peptides; D010047:Ovalbumin