TAM receptors are fundamental inhibitors of the innate immune response in sentinel cells of the immune system. Pathogen encounter by dendritic cells (DCs) and macrophages triggers a rapid inflammatory response that is essential to combating infection. However, this response must be tightly regulated, since unrestrained Toll-like receptor (TLR) and cytokine receptor signaling generates a chronic inflammatory milieu that often leads to autoimmune disease. We have found that the TAM receptor tyrosine kinases - Tyro3, Axl, and Mer - broadly inhibit both TLR and TLR-induced cytokine receptor cascades^{1, 2}. Remarkably, TAM inhibition of inflammation is transduced through an essential stimulator of inflammation - the type I interferon receptor (IFNAR) and its associated transcription factor STAT1. TLR induction of IFNAR-STAT1 signaling up-regulates components of the TAM system, which in turn usurp the IFNAR-STAT1 cassette to induce the cytokine and TLR suppressors SOCS1 and SOCS3. These events delineate a self-regulating cycle of inflammation, in which the obligatory, cytokine-dependent activation of TAM signaling hijacks a pro-inflammatory pathway to provide an intrinsic feedback inhibitor of both TLR- and cytokine-driven immune responses. We are currently studying how both inflammatory (e.g., LPS, poly I:C) and immunosuppressive (e.g., IL-10, glucocorticoids) stimuli differentially regulate TAM receptor expression in DCs, macrophages, and Langerhans cells³; and the consequences of this differential regulation for sentinel cell function.

1. Rothlin, C.V., Ghosh, S., Zuniga, E.I., Oldstone, M.B. and Lemke, G. (2007) TAM Receptors are pleiotropic inhibitors of the innate immune response. Cell 131: 1124-36.
2. Lemke, G. and Rothlin, C.V. (2008) Immunobiology of the TAM receptors. Nat. Rev. Immunol. 8: 327-36.
3. Bauer, T., Zagórska, A., Jurkin, J.,  Yasmin, N., Köffel, R., Richter, S., Gesslbauer, B., Lemke, G.,  and Strobl, H. (2012) Identification of Axl as a downstream effector of TGF-β1 during Langerhans cell differentiation and epidermal homeostasis. J. Exp. Med. 209: 2033-2047.