期刊
AUTOIMMUNITY
卷 41, 期 7, 页码 501-511出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/08916930802069256
关键词
CD4(+) Th; pMHC I; dendritic cells; membrane acquisition; diabetes
类别
资金
- Canadian Institute of Health Research (CIHR) [79415, 81228]
- Postdoctoral Fellowship of Saskatchewan Health Research Foundation
CD4(+) helper T (Th) cells play crucial role in priming, expansion and survival of CD8(+) cytotoxic T lymphocytes (CTLs). However, how CD4(+) Th cell's help is delivered to CD8+ T cells in vivo is still unclear. We previously demonstrated that CD4+ Th cells can acquire ovalbumin (OVA) peptide/major histocompatibility complex (pMHC I) and costimulatory CD80 by OVA-pulsed DC (DCOVA) stimulation, and then stimulate OVA-specific CD8(+) CTL responses in C57BL/6 mice. In this study, we further investigated CD4(+) Th cell's effect on stimulation of CD8 CTL responses in major histocompatibility complex (MHC II) gene knockout (KO) mice and transgenic rat insulin promoter (RIP)-mOVA mice with moderate expression of self OVA by using CD4(+) Th cells or Th cells with various gene deficiency. We demonstrated that the in vitro DCOVA-activated CD4(+) Th cells (3 x 10(6) cells/mouse) can directly stimulate OVA-specific CD8(+) T-cell responses in wild-type C57BL/6 mice and MHC II gene KO mice lacking CD4(+) T cells. A large amount of CD4(+) Th cells (12 X 10(6) cells/mouse) can even overcome OVA-specific immune tolerance in transgenic RIP-mOVA mice, leading to CD8(+) CTL-mediated mouse pancreatic islet destruction and diabetes. The stimulatory effect of CD4(+) Th cells is mediated by its IL-2 secretion and CD40L and CD80 costimulations, and is specifically delivered to OVA-specific CD8(+) T cells in vivo via its acquired pMHC I complexes. Therefore, the above elucidated principles for CD4(+) Th cells will have substantial implications in autoimmunity and antitumor immunity, and regulatory T-cell-dependent immune suppression.
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