title: Balance between NF-κB p100 and p52 regulates T cell costimulation dependence.
abstract: c-IAP1 and c-IAP2 are ubiquitin protein ligases (E3s) that repress noncanonical NF-κB 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-γ to stimulation via TCR alone. c-IAP2(H570A) T cells had constitutive noncanonical NF-κB activation, and IκB 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-κB, were also costimulation independent, consistent with the negative role of this unprocessed protein in canonical NF-κB 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.
authors.affiliation: Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Giardino Torchia
authors.forename: Dietrich B
authors.initials: DB
authors.lastname: Conze
authors.forename: Dragana
authors.initials: D
authors.lastname: Jankovic
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ashwell
mesh_terms: D000818:Animals; D004789:Enzyme Activation; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D007156:Immunologic Memory; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D052003:NF-kappa B p52 Subunit / Q000737:chemistry / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D014122:Toxoplasma / Q000276:immunology; D014123:Toxoplasmosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D007376:Interleukin-2; D052003:NF-kappa B p52 Subunit; D007371:Interferon-gamma; D051550:I-kappa B Kinase