Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus

Thymocytes mature in a series of stages by migrating through specific areas of the thymus and interacting with other cells to receive the necessary developmental signals; however, little is known about the molecular mechanisms governing this migration. We report that murine thymocytes with a knockout mutation in α-PAK (p21-activated kinase)-interacting exchange factor (PIX; Arhgef6), an activator of Rho GTPases, showed greatly increased motility and altered morphology in two-dimensional migration on ICAM-1. αPIX was also required for efficient positive selection, but not negative selection, of thymocytes. TCR signaling was normal in αPix− thymocytes, indicating that the effects of αPIX on positive selection are largely independent of TCR signaling. αPix− thymocytes also paused less during migration in the thymic cortex, interacted less with ICAM-1 coated beads, and could overcome TCR stop signals, consistent with defective scanning behavior. These results identify αPIX as a regulator of thymocyte migration and subsequent arrest that is linked to positive selection.

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

αPIX RhoGEF Supports Positive Selection by Restraining Migration and Promoting Arrest of Thymocytes

Korthals

Schilling

Reichardt

et al. 2014

“…Mst1/2 proteins may also promote apoptosis by interacting and suppressing Akt activation in cancer cells (22). However, T cells from Mst1-deficient mice and human patients exhibit enhanced apoptosis (23)(24)(25) in addition to the mutant phenotypes of impaired adhesion and migration in mice (25)(26)(27)(28)(29), suggesting that Mst1 may exert different cellular functions in tissue/cell type-specific manners (28 …”

Section: Mst2mentioning

confidence: 99%

Mst1/Mst2 Regulate Development and Function of Regulatory T Cells through Modulation of Foxo1/Foxo3 Stability in Autoimmune Disease

Shi

et al. 2014

122

126

Foxp3 expression and regulatory T cell (Treg) development are critical for maintaining dominant tolerance and preventing autoimmune diseases. Human MST1 deficiency causes a novel primary immunodeficiency syndrome accompanied by autoimmune manifestations. However, the mechanism by which Mst1 controls immune regulation is unknown. In this article, we report that Mst1 regulates Foxp3 expression and Treg development/function and inhibits autoimmunity through modulating Foxo1 and Foxo3 (Foxo1/3) stability. We have found that Mst1 deficiency impairs Foxp3 expression and Treg development and function in mice. Mechanistic studies reveal that Mst1 enhances Foxo1/3 stability directly by phosphorylating Foxo1/3 and indirectly by attenuating TCR-induced Akt activation in peripheral T cells. Our studies have also shown that Mst1 deficiency does not affect Foxo1/3 cellular localization in CD4 T cells. In addition, we show that Mst1−/− mice are prone to autoimmune disease, and mutant phenotypes, such as overactivation of naive T cells, splenomegaly, and autoimmune pathological changes, are suppressed in Mst1−/− bone marrow chimera by cotransplanted wt Tregs. Finally, we demonstrate that Mst1 and Mst2 play a partially redundant role in Treg development and autoimmunity. Our findings not only identify Mst kinases as the long-searched-for factors that simultaneously activate Foxo1/3 and inhibit TCR-stimulated Akt downstream of TCR signaling to promote Foxp3 expression and Treg development, but also shed new light on understanding and designing better therapeutic strategies for MST1 deficiency–mediated human immunodeficiency syndrome.

“…Negative selection against tissuespecific Ags and development of regulatory T cells (Tregs) occurs in the medulla for several days before the SP cells exit to the periphery, which is suitable for scanning over limited time periods for rare tissue-specific Ags that are expressed by Aire + ICAM-1 high medullary epithelial cells (10). Whereas OT-I CD8 thymocytes showed multiple contacts with medullary dendritic cells (DCs) in negatively selecting environments (11), two-photon imaging of OT-II CD4 thymocytes in the presence of cognate thymic tissues revealed frequent arrest and cluster formation of CD4 SP cells on Aire + ICAM-1 high medullary TECs (12). Upon activation by chemokines and TCR stimulation, the small GTPase Rap1 serves as a potent activator of integrins.…”

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confidence: 99%

Sema3e/Plexin D1 Modulates Immunological Synapse and Migration of Thymocytes by Rap1 Inhibition

Ueda

Kondo

Ozawa

et al. 2016

Self Cite

Regulation of thymocyte trafficking plays an important role during thymic selection, but our understanding of the molecular mechanisms underlying these processes is limited. In this study, we demonstrated that class III semaphorin E (sema3e), a guidance molecule during neural and vascular development, directly inhibited Rap1 activation and LFA-1–dependent adhesion through the GTPase-activating protein activity of plexin D1. Sema3e inhibited Rap1 activation of thymocytes in response to chemokines and TCR stimulation, LFA-mediated adhesion, and T cell–APC interactions. Immunological synapse (IS) formation in mature thymocytes on supported lipid bilayers was also attenuated by sema3e. Impaired IS formation was associated with reduced Rap1 activation on the contact surface and cell periphery. Moreover, a significant increase of CD4+ thymocytes was detected in the medulla of mice with T cell lineage–specific deletion of plexin D1. Two-photon live imaging of thymic explants and slices revealed enhanced Rap1 activation and migration of CD69+ double-positive and single-positive cells with plexin D1 deficiency. Our results demonstrate that sema3e/plexin D1 modulates IS formation and Ag-scanning activities of thymocytes within thymic tissues.