Analysis of signaling events regulating immune cell activation.

We have successfully demonstrated that the transmembrane adaptor SIT inhibits TCR-mediated signals required for (i) thymocyte selection, (ii) peripheral T-cell homeostasis, and (iii) peripheral T-cell functions. Additionally, we have shown that loss of SIT enhances the susceptibility to develop spontaneous or experimentally induced autoimmune diseases. We have also shown that SIT and the structurally related molecules TRIM and LAX functionally overlap. Whereas SIT and TRIM represent two negative regulators that together set the signaling threshold for positive selection, SIT and LAX cooperatively inhibit the expansion of peripheral CD4+ T cells and limit autoimmunity. In summary, our studies have demonstrated that transmembrane adaptor molecules represent critical regulators in lymphocyte biology that possess redundant functions. We have further investigated how transmembrane adaptors regulate TCR-mediated signaling. We found that SIT inhibits proximal TCR signaling and the Akt-Foxo pathway, thus suppressing T-cell proliferation. On the basis of these findings, we propose (i) the further characterization of how SIT regulates proximal TCR signaling and (ii) the investigation of the functional redundancy between SIT/TRIM and SIT/LAX at a molecular level.