Immune response - CD137 signaling in immune cell

CD137 signaling in immune cell

CD137(TNFRSF9) is an inducible T cell surface receptor belonging to the tumor necrosis factor receptor superfamily. It presents on the surfaces of activated CD4+ and CD8+ T cells, monocytes and B lymphocytes. CD137(TNFRSF9) signaling is activated by binding to its high-affinity ligand CD137 ligand(TNFSF9) expressed on the antigen-presenting cell surface. CD137(TNFRSF9) signaling promotes cell growth, T cell differentiation and survival (see anti-apoptosis of immune cells [1], [2].

CD137(TNFRSF9) mediates its action via association with TRAF1 and TRAF2. CD137(TNFRSF9) binding to TRAF2 leads to activation of the NIK(MAP3K14). NIK(MAP3K14) activates NF-kB via the IKK-alpha/ NFKBIA pathway [2], [3], [4]. NF-kB induces transcription of Bcl-XL, Bcl-2 and BFL1, and thus promotes survival (see anti-apoptosis of immune cells [5], [6], [7].

In addition, activation of NF-kB stimulates expression of IL-2, IL-4 and IFN-gamma [2], [8].

CD137(TNFRSF9) binding to TRAF2 also promotes activation of the ASK1 (MAP3K5). ASK1 (MAP3K5) induces JNK1(MAPK8) and p38 MAPK activation via MEK3(MAP2K3), MEK4(MAP2K4) and MEK6(MAP2K6). JNK1(MAPK8) and p38 MAPK phosphorylate ATF-2 and c-Jun. Activation of ATF-2 and c-Jun also induces production of IL-2, IL-4 and IFN-gamma and leads to Th1 and Th2 cell development (see T-helper cell differentiation [9], [10].

Also, CD137(TNFRSF9) association with TRAF1 and TRAF2 leads to ERK1/2 activation via TRAF1 stimulation of ERK1/2 activity and possible TRAF2/ NIK(MAP3K14)/ MEKK1(MAP3K1)/ MEK1(MAP2K1) pathway [7], [11], [12], [13]. ERK1/2 activation leads to Cyclin D2 transcription possibly via c-Jun. In addition, CD137(TNFRSF9)-induced IL-2 signaling triggers translation of Cyclin D2 protein [7], [14]. Cyclin D2 stimulates expression of Cyclin E and this leads to cell cycle progression (see positive regulation of cell cycle) and promotes cell proliferation of CD4-positive and CD8-positive cells under CD137(TNFRSF9) control [11], [14], [15], [16], [17], [18], [19].

CD137(TNFRSF9)-induced ERK1/2 activation also leads to Bim phosphorylation by ERK1/2. It promotes proteosomal degradation of Bim and leads to immune cell survival [13], [19].

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References:

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