Immunobiology of the TAM receptors

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Abstract
The TAM receptor protein tyrosine kinases — TYRO3, AXL and MER — have important roles in the immune, nervous, reproductive and vascular systems. Two closely related proteins — growth-arrest-specific 6 (GAS6) and protein S — function as TAM ligands. Mutant mice that lack all three TAM receptors are viable, but exhibit a plethora of phenotypes, all of which appear to be degenerative rather than developmental in nature. Mice deficient in all three TAM receptors develop a severe lymphoproliferative disorder accompanied by broad-spectrum autoimmune disease. These immune phenotypes reflect a loss of TAM function in dendritic cells (DCs), macrophages and natural killer (NK) cells, rather than in lymphocytes. Recent studies have revealed that autoimmunity in TAM triple mutants results from the loss of TAM-mediated regulation of two phenomena: the inhibition of the innate inflammatory response to pathogens by DCs and macrophages, and the phagocytosis of apoptotic cells by these antigen-presenting cells. Both TAM-mediated inhibition of inflammation and TAM-mediated stimulation of NK-cell differentiation require an intimate signalling interaction between TAM receptors and cytokine receptors, and this may prove to be a general feature of TAM action in the immune system. The discovery of TAM receptor function illuminates novel targets for therapeutic intervention. Future studies focused on the selective activation or inhibition of this receptor family may lead to new therapies for chronic inflammatory diseases and new vaccine adjuvants, respectively.