The complement receptor CD46 tips the scales in TH1 self-control

IFN-γ – IL-10 + T H 1 cells in response to T cell antigen receptor (TCR)-mediated activation (Fig. 1). Importantly, this switch is strictly IL-2 dependent: at low IL-2 concentrations, CD3-and CD46-stimulated helper T cells produce almost exclusively IFN-γ (Fig. 1a,b), whereas high IL-2 drives production of IL-10 (Fig. 1c). Notably, even with high IL-2, T cells exclusively produce IFN-γ at early time points (24 h) and become IL-10 producers later (72 h). The rapid and exclusive induction of fully armed T H 1 effector cells early in infection makes func-tional sense because it controls microorgan-isms at local sites. Additional antigen-specific complement activation and ligation of CD46 by C3b-or C4b-opsonized microorganisms might serve as a feedback mechanism to prevent dele-terious effects of high-IFN-γ CD4 + T cells and/ or as a physiologic termination pathway of T H 1 effector responses. In line with this view, the authors demonstrate autocrine IL-2 produc-tion in CD46-activated T cells, with a domi-nant role for IFN-γ + but not IL-10 + T cells, and link this differential behavior to the induction of high nuclear levels of inducible cAMP early response/cAMP response element modulator (ICER/CREM) in IL-10-producing T cells. The induction of ICER/CREM in effector T cells has been shown to attenuate IL-2 production as a potential mechanism of regulatory T cell– mediated suppression 5 . In search of mechanisms that account for the CD46-specific induction of IL-10, Cardone et al. 4 demonstrate a new signal-ing pathway downstream of the cytoplasmic domain 1 (CYT-1) of CD46. As a result of alternative splicing, CD46 can be expressed with two distinct cytoplasmic domains, known as CYT-1 or CYT-2. Although a pre-vious study has shown that CYT-1 is crucial to IL-10 production from CD4 + T lymphocytes 6 , The mechanisms driving IL-10 production by human T helper type 1 effector cells are poorly defined. New data link the complement regulator protein CD46 to this process and suggest an important role in autoimmune arthritis. T he role of complement in early host defense is quite well understood. Complement senses conserved exogenous and endogenous danger motifs in the fluid phase through C1q and mannan-binding lectin (MBL). Subsequent activation of the complement cascade generates cleavage fragments of C3 and C5, translating this information into cellular signals through the activation of specific complement recep-tors. Such cellular responses are not restricted to the innate immune system but also regulate the development and maintenance of B and T cell responses 1 . Membrane cofactor pro-tein (MCP; CD46), a type I transmembrane protein, is a complement receptor comprising four conserved complement control repeats, a serine-, threonine-and proline-rich region, and then a transmembrane segment and an intracytoplasmic tail. Traditionally, CD46 has been considered a membrane-bound regula-tor protein protecting cells from complement attack. In addition to its complement-regulatory properties, CD46 serves as a pathogen receptor for measles virus, herpesvirus 6, adenoviruses, pathogenic Neisseria spp. and Streptococcus pyogenes. Previously, co-stimulation of human CD4 + T lymphocytes with CD46 has been described as inducing T regulatory type 1 cell– like lymphocytes that produce abundant IL-10 (ref. 2). Interestingly, such cells also produce substantial amounts of interferon (IFN)-γ, reminiscent of T helper type 1 (T H 1) effector lymphocytes that produce IL-10 (ref. 3). In this issue of Nature Immunology, Cardone et al. show that CD46 activation drives the switch from classical IFN-γ-producing T H 1 effector cells toward IL-10-producing T H 1 cells with immunosuppressive properties 4 . CD4 + T effector lymphocytes can be differ-entiated into three major subsets—T H 1, T H 2 and T H 17 cells—each characterized by signa-ture transcription factors that mediate their lineage commitment and hallmark cytokines that drive their effector functions. In addition to their signature effector cytokines IFN-γ (T H 1), IL-4 (T H 2) or IL-17 (T H 17), all helper T cell subsets can produce IL-10, a cytokine with broad immunoregulatory properties. The induction of IL-10 in helper T effector cells might serve as an autoregulatory mechanism of adaptive immunity to prevent cell and tis-sue damage by activated T effector lympho-cytes in infectious, autoimmune and allergic diseases 3 . The flip side is that IL-10-producing T H 1 effector cells can be exploited by intracel-lular pathogens to prevent their clearance, as occurs, for example, in Leishmania infection 3 . In mice, several pathways have been described that promote IL-10 production in T H 1 cells, including T cell activation by plasmacytoid dendritic cells through the Notch receptor and the co-stimulatory molecule ICOS as well as in response to high antigen exposure in the presence of high IL-12 or IL-27 (ref. 3). The regulatory pathways leading to IL-10 produc-tion in human CD4 + T H 1 effector cells are as yet ill defined. The study by Cardone et al. 4 demonstrates a CD46-mediated switch from IFN-γ-producing T H 1 effector cells to IFN-γ + IL-10 + and