Balance between NF-κB p100 and p52 regulates T cell costimulation dependence

• Published in: The Journal of immunology (1950) 2013-01, Vol.190 (2), p.549-555
• Main Authors: Giardino Torchia, Maria Letizia, Conze, Dietrich B, Jankovic, Dragana, Ashwell, Jonathan D
• Format: Article
• Language: English
• Subjects: Animals; Enzyme Activation; I-kappa B Kinase - antagonists & inhibitors; Immunologic Memory; Inhibitor of Apoptosis Proteins - genetics; Inhibitor of Apoptosis Proteins - immunology; Interferon-gamma - biosynthesis; Interferon-gamma - immunology; Interleukin-2 - biosynthesis; Interleukin-2 - immunology; Lymphocyte Activation - immunology; Mice; Mice, Knockout; Mutation; NF-kappa B p52 Subunit - chemistry; NF-kappa B p52 Subunit - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Toxoplasma - immunology; Toxoplasma gondii; Toxoplasmosis - genetics; Toxoplasmosis - immunology; Toxoplasmosis - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1201697

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.