T follicular helper (T FH ) cells provide critical help to B cells during humoral immune responses.Here we report that mice with T cell-specific deletion of miR-17~92 family miRNAs (tKO mice) exhibited severely compromised T FH differentiation, germinal center formation, antibody responses, and failed to control chronic virus infection. Conversely, T cell-specific miR-17~92 transgenic mice spontaneously accumulated T FH cells and developed fatal immunopathology. Mechanistically, miR-17~92 family miRNAs control CD4 + T cell migration into B cell follicles by regulating ICOS-PI3K signaling intensity through suppressing the expression of the Akt phosphatase Phlpp2. These findings demonstrate that miR-17~92 family microRNAs play an essential role in T FH differentiation and establish Phlpp2 as an important mediator of their function in this process.MicroRNAs (miRNAs) are endogenously encoded small RNAs of ~22 nucleotides in length that play important roles in a large diversity of biological processes 1,2,3 .

The physiological activity of Notch is a function of its ability to increase survival in many cell types. Several pathways have been shown to contribute to the survival effect of Notch, but the exact mechanism of Notch action is not completely understood. Here we identified that the regulation of cell survival by Notch intracellular domain could partly be attributed to a selective increase of X‐linked inhibitor of apoptosis protein (XIAP). We further found that Notch intracellular domain inhibited the degradation of XIAP during apoptosis. The transactivation domain of Notch interacted directly with the RING region of XIAP to block the binding of E2 and prevent the in vivo and in vitro ubiquitination of XIAP. This antiapoptotic activity of Notch was abolished when XIAP was knocked down. Our results reveal a novel mechanism for Notch‐selective suppression of apoptosis through an increase in the stability of a key antiapoptotic protein, XIAP.

The molecular process underlying T cell anergy is incompletely understood. Deltex1 (DTX1) is a Notch target with unknown physiological function. Here we show that Dtx1 was a transcription target of nuclear factor of activated T cells (NFAT) and participated in T cell anergy. DTX1 protein was upregulated during T cell anergy, and transgenic expression of Dtx1 attenuated T cell activation. DTX1 inhibited T cell activation by both E3-dependent and E3-independent mechanisms. In addition, DTX1 suppressed T cell activation in the absence of its Notch-binding domain. Importantly, DTX1 regulated the expression of two anergy-associated molecules, growth arrest and DNA-damage-inducible 45 beta (Gadd45 beta) and Cbl-b. DTX1 interacted with early growth response 2 (Egr-2) for optimum expression of Cbl-b. Furthermore, deficiency of DTX1 augmented T cell activation, conferred resistance to anergy induction, enhanced autoantibody generation, and increased inflammation. DTX1 therefore represents a component downstream of calcium-NFAT signaling that regulates T cell anergy.

Application of regulatory T cells (Tregs) in transplantation, autoimmunity and allergy has been extensively explored, but how Foxp3 and Treg stability is regulated in vivo is incompletely understood. Here, we identify a requirement for Deltex1 (DTX1), a contributor to T-cell anergy and Foxp3 protein level maintenance in vivo. Dtx1−/− Tregs are as effective as WT Tregs in the inhibition of CD4+CD25− T-cell activation in vitro. However, the suppressive ability of Dtx1−/− Tregs is greatly impaired in vivo. We find that Foxp3 expression is diminished when Dtx1−/− Tregs are co-transferred with effector T cells in vivo. DTX1 promotes the degradation of HIF-1α. Knockout of HIF-1α restores the Foxp3 stability and rescues the defective suppressive activity in Dtx1−/− Treg cells in vivo. Our results suggest that DTX1 exerts another level of control on Treg stability in vivo by sustaining the expression of Foxp3 protein in Tregs.

Deltex is known as a Notch signal mediator, but its physiological action mechanism is poorly understood.