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Balanced control of T cell signaling is critical for adaptive immunity and protection from autoimmunity. By combining genetically engineered mouse models, biochemical analyses and pharmacological interventions, we describe an unexpected dual role of the tumor necrosis factor receptor–associated factor 6 (TRAF6) E3 ligase as both a positive and negative regulator of mucosa-associated lymphoid tissue 1 (MALT1) paracaspase. Although MALT1-TRAF6 recruitment is indispensable for nuclear factor κB signaling in activated T cells, TRAF6 counteracts basal MALT1 protease activity in resting T cells. In mice, loss of TRAF6-mediated homeostatic suppression of MALT1 protease leads to severe autoimmune inflammation, which is completely reverted by genetic or therapeutic inactivation of MALT1 protease function. Thus, TRAF6 functions as a molecular brake for MALT1 protease in resting T cells and a signaling accelerator for MALT1 scaffolding in activated T cells, revealing that TRAF6 controls T cell activation in a switch-like manner. Our findings have important implications for development and treatment of autoimmune diseases.

Peripheral tolerance is an important strategy used by the immune system to prevent self-reactive lymphocytes from attacking host tissues. A variety of mechanisms contribute to peripheral tolerance, among them activation-induced cell death, suppression by regulatory T cells, and T cell anergy or unresponsiveness. Recent work has led to a better understanding of the cell-intrinsic program that establishes T cell anergy. A major insight is that during the induction phase of anergy, incomplete stimulation (T cell receptor stimulation without costimulation) leads via calcium influx to an altered gene expression program that includes up-regulation of several E3 ubiquitin ligases. When the anergic T cells contact antigen-presenting cells, intracellular signaling proteins are monoubiquitinated and targeted for lysosomal degradation, thus decreasing intracellular signaling and also resulting in decreased stability of the T cell–antigen-presenting cell contact. We propose a molecular program leading to T cell anergy and discuss other proteins that may play a role.