Novel Regulation of CD80/CD86-induced Phosphatidylinositol 3-kinase Signaling by Notch1 in IL-6 and Indoleamine 2,3 dioxygenase Production by Dendritic Cells [Immunology]

January 10th, 2014 by Koorella, C., Nair, J. R., Murray, M. E., Carlson, L. M., Watkins, S. K., Lee, K. P.

Dendritic cells (DC) play a critical role in modulating antigen-specific immune responses elicited by T cells via costimulation. It is well known that engagement of the T cell costimulatory receptor CD28 by its ligands CD80/CD86 results in T cell activation. However, only recently it has been shown that CD80/CD86 are not mere ligands but can also signal. Functionally, CD80/CD86 engagement results in DC production of the pro-inflammatory cytokine IL-6, which activates T cells. On the other hand, CTLA4-mediated ligation of CD80/CD86 induces DC production of the immunosuppressive enzyme indoleamine 2, 3 dioxygenase (IDO), which catabolizes the essential amino acid tryptophan, and blocks T cell activation. Despite these significant and seemingly opposing immunological roles, how CD80/CD86 signal remains poorly understood. We have now found that crosslinking CD80/CD86 in human DC activates the PI3K/Akt pathway with subsequent phosphorylation/inactivation of its downstream target FoxO3a, which alleviates FoxO3a-mediated IL-6 suppression. Simultaneous activation of the canonical NF-κB pathway induces IL-6 expression. Unexpectedly, this PI3K signaling is regulated by previously unrecognized crosstalk with Notch1 signaling which inactivates/phosphorylates PTEN (which suppresses PI3K activity) via Pin1-mediated upregulation of casein kinase II activity. This allows for full PI3K activation by CD80/CD86. Similar to IL-6, we have found that CD80/CD86-induced late IDO production by DC via the PI3K->Akt->NF-κB pathway, and requires crosstalk with Notch1 signaling. In addition to characterizing how CD80/CD86-mediates IL-6 and IDO production, identification of a novel crosstalk between Notch1 and PI3K signaling may provide new insights in other biological processes where PI3K signaling plays a major role.
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