期刊
JOURNAL OF IMMUNOLOGY
卷 190, 期 2, 页码 549-555出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1201697
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资金
- Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute
c-IAP1 and c-IAP2 are ubiquitin protein ligases (E3s) that repress noncanonical NF-kappa B activation. We have created mice that bear a mutation in c-IAP2 that inactivates its E3 activity and interferes, in a dominant-negative fashion, with c-IAP1 E3 activity (c-IAP2(H570A)). The immune response of these animals was explored by infecting them with the Th1-inducing parasite Toxoplasma gondii. Surprisingly, c-IAP2(H570A) mice succumbed because of T cell production of high levels of proinflammatory cytokines. Unlike naive wild-type (WT) cells, which require signals generated by the TCR and costimulatory receptors to become fully activated, naive c-IAP2(H570A) T cells proliferated and produced high levels of IL-2 and IFN-gamma to stimulation via TCR alone. c-IAP2(H570A) T cells had constitutive noncanonical NF-kappa B activation, and I kappa B kinase inhibition reduced their proliferation to anti-TCR alone to WT levels but had no effect when costimulation via CD28 was provided. Notably, T cells from nfkb2(-/-) mice, which cannot generate the p52 component of noncanonical NF-kappa B, were also costimulation independent, consistent with the negative role of this unprocessed protein in canonical NF-kappa B activation. Whereas T cells from nfkb2(+/-) mice behaved like WT, coexpression of a single copy of c-IAP2(H570A) resulted in cleavage of p100, upregulation of p52, and T cell costimulation independence. Thus, p100 represses and p52 promotes costimulation, and the ratio regulates T cell dependence on costimulatory signals. The Journal of Immunology, 2013, 190: 549-555.
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