Signaling through the NF-kB pathway is of critical importance for T and B lymphocyte maturation, maintenance and function. It is also involved in autoimmune reactions performed by these cells and contributes to the survival of certain classes of B cell lymphomas. Critical components in this pathway are the IkB-kinases (IKKs) which activate NF-kB signaling upon their own activation by pro-inflammatory and antigen receptor mediated signals delivered to the cells. IKK signaling can either involve the IKK signal some consisting of IKK1, IKK2 and the NEMO protein, or proceed through IKK1 activation alone. The underlying hypothesis of the present proposal is that the activation of these two pathways, either in combination or separately, is essential for T and B cells to mature, survive and perform their various functions, and also for the promotion of certain B cell malignancies. We will therefore explore in which way the inactivation of either pathway, or its enforced activation, affect the maturation, functional activities and malignant transformation of T and/or B cells at various stages of development. Rescue experiments will identify the downstream targets of IKK signaling which are responsible for cellular maintenance, and also establish whether IKK signaling is sufficient for cellular survival in the absence of receptors such as the antigen and BAFF receptor, known to be required for B cell maintenance in normal physiology. We will also define the role of cell-autonomous IKK signals in T and B cell mediated autoreactivity. Cell type-specific activation and inactivation of IKKs will be used for this purpose, exploiting techniques of conditional gene targeting which we have established in the past. ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunobiology Study Section (IMB)
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Peyman, John A
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Immune Disease Institute, Inc.
United States
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Dong, Jing; Levine, David M; Buas, Matthew F et al. (2018) Interactions Between Genetic Variants and Environmental Factors Affect Risk of Esophageal Adenocarcinoma and Barrett's Esophagus. Clin Gastroenterol Hepatol 16:1598-1606.e4
Otipoby, Kevin L; Waisman, Ari; Derudder, Emmanuel et al. (2015) The B-cell antigen receptor integrates adaptive and innate immune signals. Proc Natl Acad Sci U S A 112:12145-50
Levine, David M; Ek, Weronica E; Zhang, Rui et al. (2013) A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus. Nat Genet 45:1487-93
Freedman, Neal D; Murray, Liam J; Kamangar, Farin et al. (2011) Alcohol intake and risk of oesophageal adenocarcinoma: a pooled analysis from the BEACON Consortium. Gut 60:1029-37
Derudder, Emmanuel; Cadera, Emily J; Vahl, J Christoph et al. (2009) Development of immunoglobulin lambda-chain-positive B cells, but not editing of immunoglobulin kappa-chain, depends on NF-kappaB signals. Nat Immunol 10:647-54
Otipoby, Kevin L; Sasaki, Yoshiteru; Schmidt-Supprian, Marc et al. (2008) BAFF activates Akt and Erk through BAFF-R in an IKK1-dependent manner in primary mouse B cells. Proc Natl Acad Sci U S A 105:12435-8
Sasaki, Yoshiteru; Calado, Dinis P; Derudder, Emmanuel et al. (2008) NIK overexpression amplifies, whereas ablation of its TRAF3-binding domain replaces BAFF:BAFF-R-mediated survival signals in B cells. Proc Natl Acad Sci U S A 105:10883-8
Rajewsky, Klaus; von Boehmer, Harald (2008) Lymphocyte development: overview. Curr Opin Immunol 20:127-30
Schmidt-Supprian, Marc; Wunderlich, F Thomas; Rajewsky, Klaus (2007) Excision of the Frt-flanked neo (R) cassette from the CD19cre knock-in transgene reduces Cre-mediated recombination. Transgenic Res 16:657-60
Liu, Huifei; Schmidt-Supprian, Marc; Shi, Yujiang et al. (2007) Yin Yang 1 is a critical regulator of B-cell development. Genes Dev 21:1179-89

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