Steroid receptor coactivator 2 belongs to a family of SRC coactivators, which orchestrate transcription programs critical for multiple cellular functions. However, the function of SRCs especially SRC2 in the immune system has long been ignored. Here, we show that SRC2 functions as a coactivator for c-Myc to stimulate the expression of amino acid transporter Slc7a5 required for T cell activation. Uncontrolled activation of T cells is responsible for various autoimmune diseases such as multiple sclerosis and immunological bowel disease and thus inhibiting the activity of SRC2 hypothetically can prevent such T cell-mediated autoimmunity. Our study not only reveals an important mechanism for SRC2-regulated T cell activation but also identifies SRC2 as a potential therapeutic target for T cell-mediated autoimmune diseases.

Ovarian reserve is an important determinant of a woman’s reproductive potential, and women with diminished ovarian reserve (DOR) often seek in vitro fertilization (IVF). The underlying etiology of DOR is unknown, but follicular fluid cytokine concentrations likely play a role in follicular development and maturation. The present study seeks to investigate the expression of cytokines in follicular fluid (FF) of women with DOR undergoing IVF and explore correlated functional pathways. 194 women undergoing ovarian stimulation were recruited at the time of oocyte retrieval. Women were classified as having DOR if they met one or more of the following criteria: AMH <1 ng/ml, FSH >10 mIU/ml and/or AFC <10. Controls included women undergoing IVF for male factor, tubal factor due to tubal ligation, or planned oocyte cryopreservation (non-oncologic). The concentrations of 480 cytokines and related growth factors in follicular fluid were determined using a multiplex immunoassay. Fifty-nine (59) cytokines had significantly different concentrations (53 higher and 6 lower) in the DOR relative to the control group after adjusting for age and body mass index (BMI) (false discovery rate; FDR<0.1). Using the most informative 44 biomarkers as indicated by a random forest (RF) model, an area under the curve (AUC) of 0.78 was obtained. Thus, follicular microenvironment differs between women with DOR and normal ovarian reserve. The differentially expressed cytokines belong to diverse processes that are primarily involved in follicular maturation and ovulation. These changes may play an important role in treatment outcomes in women with DOR.

Survival of T cells in both the central and peripheral immune system determines its ultimate function in the regulation of immune responses. In the thymus, developing T cells undergo positive and negative selection to generate a T cell repertoire that responds to foreign, but not self, antigens. During T cell development, the T cell receptor chain is rearranged. However, the first round of rearrangement may fail, which triggers another round of chain rearrangement until either successful positive selection or cell death occurs. Thus, the lifespan of double positive (CD 4 CD 8 ; DP) thymocytes determines how many rounds of chain rearrangement can be carried out and influences the likelihood of completing positive selection. The anti-apoptotic protein Bcl-x L is the ultimate effector regulating the survival of CD 4 CD 8 + thymocytes subject to the selection process, and the deletion of Bcl-x L leads to premature apoptosis of thymocytes prior to the completion of the developmental process. In addition to its critical function in the thymus, Bcl-x L also regulates the survival of peripheral T cells. Upon engagement with antigens, T cells are activated and differentiated into effectors. Activated T cells upregulate Bcl-x L to enhance their own survival. Bcl-x L -mediated survival is required for the generation of effectors that carry out the actual immune responses. In the absence of Bcl-x L , mature T cells undergo apoptosis prior to the completion of the differentiation process to become effector cells. Therefore, Bcl-x L ensures the survival of both developing and peripheral T cells, which is essential for a functional immune system.

Severe liver injury that occurs when immune cells mistakenly attack an individual's own liver cells leads to autoimmune hepatitis. In mice, acute hepatitis can be induced by concanavalin A (ConA) treatment, which causes rapid activation of CD1d-positive natural killer (NK) T cells. These activated NKT cells produce large amounts of cytokines, which induce strong inflammation that damages liver tissues. Here we show that PKC-θ -/- mice were resistant to ConA-induced hepatitis due to essential function of PKC-θ in NKT cell development and activation. A dosage of ConA (25 mg/kg) that was lethal to wild-type (WT) mice failed to induce death resulting from liver injury in PKC-θ -/- mice. Correspondingly, ConA-induced production of cytokines such as IFNγ, IL-6, and TNFα, which mediate the inflammation responsible for liver injury, were significantly lower in PKC-θ -/- mice. Peripheral NKT cells had developmental defects at early stages in the thymus in PKC-θ -/- mice, and as a result their frequency and number were greatly reduced. Furthermore, PKC-θ -/- bone marrow adoptively transferred to WT mice displayed similar defects in NKT cell development, suggesting an intrinsic requirement for PKC-θ in NKT cell development. In addition, upon stimulation with NKT cell-specific lipid ligand, peripheral PKC-θ -/- NKT cells produced lower levels of inflammatory cytokines than that of WT NKT cells, suggesting that activation of NKT cells also requires PKC-θ. Our results suggest PKC-θ is an essential molecule required for activation of NKT cell to induce hepatitis, and thus, is a potential drug target for prevention of autoimmune hepatitis.

RORγt is known to instruct the differentiation of T helper 17 (TH17) cells that mediate the pathogenesis of autoimmune diseases. However, it remains unknown whether RORγt plays a distinct role in the differentiation and effector function of TH17 cells. Here, we show that mutation of RORγt lysine-256, a ubiquitination site, to arginine (K256R) separates the RORγt role in these two functions. Preventing ubiquitination at K256 via arginine substitution does not affect RORγt-dependent thymocyte development, and TH17 differentiation in vitro and in vivo, however, greatly impaired the pathogenesis of TH17 cell–mediated experimental autoimmune encephalomyelitis (EAE). Mechanistically, K256R mutation impairs RORγt to bind to and activate Runx1 expression critical for TH17-mediated EAE. Thus, RORγt regulates the effector function of TH17 cells in addition to TH17 differentiation. This work informs the development of RORγt-based therapies that specifically target the effector function of TH17 cells responsible for autoimmunity.