IntroductionDendritic cells (DCs) are potent mediators of T-cell activation and proinflammatory immune responses to foreign antigens and pathogens. 1,2 However, DCs also have an important role in maintaining immune homeostasis and tolerance to self-proteins. [3][4][5][6][7] These 2 opposing functions are believed in part to reflect differences in DC activation, maturation, and/or subset. Tolerogenic DCs typically exhibit an immature phenotype characterized by low cell-surface expression of MHC and costimulatory molecules and do not secrete proinflammatory cytokines. Furthermore, soluble and cellular mediators that inhibit DC activation and maturation can establish a tolerogenic phenotype. For example, binding to and phagocytosis of apoptotic cells (ACs) by immature DCs inhibits activation and maturation induced by various stimuli. 8,9 This inhibitory effect serves an important role because ACs are present in tissues under both homeostatic and inflamed conditions and provide a potential source of self-proteins to mediate autoimmunity. Defective clearance of ACs has been linked to different types of autoimmunity. 10,11 A number of receptors expressed by immature DCs such as the phosphatidylserine (PS) receptor, CD36, ␣ v ␤ 5 integrin, and complement receptor C1qR are involved in AC binding and/or ingestion. [12][13][14][15] However, the relative contribution of these receptors in mediating the immunoregulatory effect(s) of ACs on immature DCs is unclear, and the molecular basis for this inhibition has not been defined in DCs.Recently, the Axl/Mer/Tyro3 receptor tyrosine kinase (RTK) family has been implicated in homeostatic regulation of antigenpresenting cell (APC) activation. 16,17 This family, consisting of Axl, Tyro3, and MerTK, is expressed by a variety of cell types, including macrophages (Ms) and DCs. Mice lacking expression of all 3 RTKs exhibit hyperactivated Ms and DCs, which in turn drive lymphoproliferation and systemic autoimmunity. 16 Similarly, our group has shown that mice lacking MerTK expression (MerT-K KD ) develop lupuslike autoimmunity and are more prone to lipopolysaccharide (LPS)-induced endotoxic shock. [18][19][20] Autoimmunity in MerTK KD mice correlates with a reduced rate of in vivo clearance of ACs, which is consistent with findings that MerTK mediates AC phagocytosis by Ms. 19,20 A ligand for MerTK is growth arrest-specific gene 6 (GAS6), which binds to PS expressed on the inverted plasma membrane of ACs. 21 Recognition of a GAS6-PS complex facilitates binding of ACs and subsequent phagocytosis by Ms. Accordingly, MerTK has been proposed to facilitate phagocytosis of ACs and down-regulate activation in Ms. [17][18][19][20] Whether MerTK functions similarly in DCs has yet to be determined.We and others [22][23][24][25][26][27] have demonstrated a key role for the transcription factor NF-B in regulating gene expression associated with the development, activation, maturation, and APC function of DCs. The NF-B complex consists of homodimers and heterodimers of the structurally related pro...

Self-antigens expressed by apoptotic cells (ACs) may become targets for autoimmunity. Tolerance to these antigens is partly established by an ill-defined capacity of ACs to inhibit antigen-presenting cells such as dendritic cells (DCs). We present evidence that the receptor tyrosine kinase Mer (MerTK) has a key role in mediating AC-induced inhibition of DC activation/maturation. Pretreatment of DCs prepared from nonobese diabetic (NOD) mice with AC blocked secretion of proinflammatory cytokines, up-regulation of costimulatory molecule expression, and T cell activation. The effect of ACs on DCs was dependent on Gas6, which is a MerTK ligand. NOD DCs lacking MerTK expression (NOD.MerTKKD/KD) were resistant to AC-induced inhibition. Notably, autoimmune diabetes was exacerbated in NOD.MerTKKD/KD versus NOD mice expressing the transgenic BDC T cell receptor. In addition, β cell–specific CD4+ T cells adoptively transferred into NOD.MerTKKD/KD mice in which β cell apoptosis was induced with streptozotocin exhibited increased expansion and differentiation into type 1 T cell effectors. In both models, the lack of MerTK expression was associated with an increased frequency of activated pancreatic CD11c+CD8α+ DCs, which exhibited an enhanced T cell stimulatory capacity. These findings demonstrate that MerTK plays a critical role in regulating self-tolerance mediated between ACs, DCs, and T cells.

The number of Foxp3+ regulatory T (Treg) cells must be tightly controlled to efficiently suppress autoimmunity while not impairing normal immune responses. Here we show that the adapter molecule TRAF3 is intrinsically required for restraining lineage determination of thymic Treg cells. T cell-specific TRAF3 deficiency resulted in a 2-3 fold increase of Treg cell frequency, due to more efficient transition from T precursors to Foxp3+ Treg cells. TRAF3 dampened interleukin-2 (IL-2) signaling by facilitating recruitment of T cell protein tyrosine phosphatase (TCPTP) to the IL-2 receptor complex, resulting in dephosphorylation of the signaling molecules Jak1 and Jak3 and negative regulation of Jak-STAT5 signaling. Our results identify a role for TRAF3 as an important negative regulator of IL-2 receptor signaling that impacts Treg cell development.

Summary A large and diverse group of receptors utilizes the family of cytoplasmic signaling proteins known as tumor necrosis factor receptor (TNFR)-associated factors (TRAFs). In recent years, there has been a resurgence of interest and exploration of the roles played by TRAF3 and TRAF5 in cellular regulation, particularly in cells of the immune system, the cell types of focus in this review. This work has revealed that TRAF3 and TRAF5 can play diverse roles for different receptors even in the same cell type, as well as distinct roles in different cell types. Evidence indicates that TRAF3 and TRAF5 play important roles beyond the TNFR-superfamily (SF) and viral mimics of its members, mediating certain innate immune receptor and cytokine receptor signals, and most recently, signals delivered by the T-cell receptor (TCR) signaling complex. Additionally, much research has demonstrated the importance of TRAF3-mediated cellular regulation via its cytoplasmic interactions with additional signaling proteins. In particular, we discuss below evidence for the participation by TRAF3 in a number of the regulatory post-translational modifications involving ubiquitin that are important in various signaling pathways.

Loss of TRAF3 results in reduced TCR signaling and defective up-regulation of T-bet and CD122 in iNKT cells that impairs their proliferation and survival.