In addition to marshalling immune and inflammatory responses, NF-kappaB controls cell survival. This control is crucial to B lymphopoiesis, T cell homeostasis, oncogenesis, and to antagonize TNFalpha-induced killing. With regard to TNFalpha the NF-kappaB anti-apoptotic activity involves the suppression of JNK signaling. Using an unbiased screen, we have identified Gadd45beta/Myd118 as a pivotal mediator of this suppression, and have found that its activity depends on direct blockade of the JNK kinase, MKK7/JNKK2. Gadd45beta is required for CD4+ T cell responses and hepato-protection from external challenge - two processes controlled in part by JNK and NF-kappaB. However, the mechanism(s) by which Gadd45beta regulates T lymphocyte function and the relevance of this regulation to adaptive immunity, in vivo, are not known. Likewise, the precise role of Gadd45beta in the liver response to injury remain to be determined. This proposal has three Specific Aims, which will address these issues concurrently.
In Aim 1, by using an in vivo approach, we will determine the physiologic function of Gadd45beta, and its control of MAPK signaling, in T cell homeostasis and adaptive immune responses. We will begin by examining kinetics of expansion and contraction of the Gadd45beta-/- T cell pool during a physiologic response to antigen. The relevance of the Gadd45beta anti-apoptotic activity to peripheral T cell deletion and memory T cell development will be established using well-characterized models.
In Aim 2, we will assess the basis for the Gadd45beta control of T cell function, during physiologic antigen-priming, ex vivo. Using this system, we will establish the precise effects of Gadd45beta ablation on T cell activation, proliferation, TH1/TH2 differentiation, and AICD. The impact of Gadd45beta on TCR-induced MAPK pathways and its consequences on T cell function will be specifically examined.
In Aim 3, we will determine the bases for the role of Gadd45beta in the liver response to injury, using well-established models of TNFalpha-induced, JNK-mediated hepato-toxicity. In particular, we will establish the relevance of the Gadd45beta control of JNK signaling to the NF-kappaB protective function in the liver. Hepatocyte function will be also studied in vitro, in the absence of any stromal or organismal influences. Altogether, these studies may provide important new insights into mechanisms of autoimmunity, chronic inflammation, and cancer, and perhaps, new therapeutic tools for their treatments.
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