The complement system is best known for its role in the early host defense response to pathogens. However, the complement receptor CD46 is present on T cells, which are part of the adaptive immune response, where it has been implicated in inducing the T regulatory type 1 response characterized by production of the anti-inflammatory cytokine interleukin-10 (IL-10). Cardone et al. investigated the temporal and molecular characteristics of the T cell response to CD46 ligation and found that human T helper 1 (TH1; CD4+) cells responded to ligation of the T cell receptor (TCR) and CD46 to produce three types of cells through a process dependent on the concentration of IL-2. When IL-2 concentrations were low, the TH1 cells produced large amounts of proinflammatory interferon-γ (IFN-γ) and little or no anti-inflammatory IL-10, whereas when IL-2 concentrations were high, TH1 cells produced little or no IFN-γ and large amounts of IL-10. This change in cytokine profile occurred over the course of 3 days, with IFN-γ production peaking after 24 hours and IL-10 production peaking after 72 hours, suggesting that the cells switched from IFN-γ+, IL-10− to IFN-γ+, IL-10+ to IFN-γ−, IL-10+. Conditions that limited TH1 differentiation substantially reduced the proportion of IFN-γ+, IL-10+ to IFN-γ−, IL-10+ cells. Additionally, the cells exposed to both CD46 and TCR ligands were positive for transcriptional markers characteristic of TH1 cells and exhibited phosphorylation of the extracellular signal–regulated kinases (ERK1 and ERK2) , consistent with the model that these type 1 regulatory cells arose from the TH1 population. CD46 can have one of two intracellular domains, depending on alternative splicing. Jurkat T cells only have the CYT-2 isoform and do not produce IFN-γ or IL-10 in response to ligation of CD46 and the TCR. However, introduction of the CYT-1 isoform of CD46 into Jurkat T cells resulted in IFN-γ and IL-10 production in response to CD46 and the TCR ligation. Another T cell population, the γδ T cells, also does not have the CYT-1 isoform and does not respond to CD46 activation by producing IL-10. Coimmunoprecipitation experiments indicated that CD46 interacted with the kinase SPAK in unstimulated TH1 cells, and TCR ligation in the absence of CD46 ligand triggered their dissociation, whereas stimulation of the TCR in the presence of CD46 ligand preserved the SPAK-CD46 interaction. Comparison of CD4+ T cells from healthy donors or patients with rheumatoid arthritis or a patient with juvenile arthritis showed that arthritis patients’ cells produced greater IFN-γ than normal controls in response to TCR and CD46 activation and that treatment of the arthritis patients’ cells with TCR and CD46 ligands failed to stimulate IL-10 production. Thus, a defective ability of TH1 cells to switch from the proinflammatory state to the anti-inflammatory state mediated by complement signaling may contribute to chronic inflammatory conditions.
J. Cardone, G. Le Friec, P. Vantourout, A. Roberts, A. Fuchs, I. Jackson, T. Suddason, G. Lord, J. P. Atkinson, A. Cope, A. Hayday, C. Kemper, Complement regulator CD46 temporally regulates cytokine production by conventional and unconventional T cells. Nat. Immunol. 11, 862–871 (2010). [PubMed]
C. M. Karsten, J. Köhl, The complement receptor CD46 tips the scales in TH1 self-control. Nat. Immunol. 11, 775–777 (2010). [Online Journal]