Editors' ChoiceImmunology

T Cells TAMing Dendritic Cells

Science Signaling  13 Aug 2013:
Vol. 6, Issue 288, pp. ec191
DOI: 10.1126/scisignal.2004609

Dendritic cells (DCs) are antigen-presenting cells that activate T cells to initiate the adaptive immune response to pathogens. Once T cells are activated, however, DC activity must be reduced; otherwise, unchecked DCs would trigger inappropriate responses, such as allergy and chronic inflammation. The TAM family members Axl and Mertk are receptor tyrosine kinases found on the surface of DCs, and they inhibit Toll-like receptor and cytokine signaling in response to the ligands Protein S (Pros1) and Gas6; however, the source of these ligands is unclear. Carrera Silva et al. found that activated mouse CD4+ T cells produced Pros1 after antigen-specific activation by DCs and that the transfer of naïve CD4+ T cells deficient in Pros1 to mice led to enhanced colitis compared with that in mice that received wild-type CD4+ T cells. In vivo, loss of Pros1 in CD4+ T cells led to enhanced activation of DCs and their increased cell-surface abundance of costimulatory molecules. When secreted by T cells, Pros1 bound to the T cell plasma membrane through its interaction with phosphatidylserines, and the ability of T cells to dampen DC activation in vitro was lost when both populations of cells were physically separated from each other. Compared with wild-type DCs, DCs deficient in both Axl and Mertk showed increased activation when cocultured with activated T cells. The authors then verified the ability of human T cells to produce Pros1 in response to activation by human DCs, and antibody-mediated blocking of ProS1 on T cells led to enhanced activation of cocultured DCs. Together, these data suggest that a Pros1-TAM signaling axis provides a negative feedback mechanism whereby T cells dampen DC activation to keep the immune response in check.

E. A. Carrera Silva, P. Y. Chan, L. Joannas, A. E. Errasti, N. Gagliani, L. Bosurgi, M. Jabbour, A. Perry, F. Smith-Chakmakova, D. Mucida, H. Cheroutre, T. Burstyn-Cohen, J. A. Leighton, G. Lemke, S. Ghosh, C. V. Rothlin, T cell-derived Protein S engages TAM receptor signaling in dendritic cells to control the magnitude of the immune response. Immunity 39, 160–170 (2013). [PubMed]