Abstract
T-cells are known to be intimately involved in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). T-cell activation is controlled by a range of intracellular signaling pathways regulating cellular responses such as proliferation, cytokine production, integrin expression, and migration. These processes are crucial for the T-cells’ ability to mediate inflammatory processes in autoimmune diseases such as MS. RhoA is a ubiquitously expressed small GTPase well described as a regulator of the actin cytoskeleton. It is essential for embryonic development and together with other Rho GTPases controls various cellular processes such as cell development, shaping, proliferation, and locomotion. However, the specific contribution of RhoA to these processes in T-cells in general, and in autoreactive T-cells in particular, has not been fully characterized. Using mice with a T-cell specific deletion of the RhoA gene (RhoAfl/flLckCre+), we investigated the role of RhoA in T-cell development, functionality, and encephalitogenic potential in EAE. We show that lack of RhoA specifically in T-cells results in reduced numbers of mature T-cells in thymus and spleen but normal counts in peripheral blood. EAE induction in RhoAfl/flLckCre+ mice results in significantly reduced disease incidence and severity, which coincides with a reduced CNS T-cell infiltration. Besides presenting reduced migratory capacity, both naïve and autoreactive effector T-cells from RhoAfl/flLckCre+ mice show decreased viability, proliferative capacity, and an activation profile associated with reduced production of Th1 pro-inflammatory cytokines. Our study demonstrates that RhoA is a central regulator of several archetypical T-cell responses, and furthermore points toward RhoA as a new potential therapeutic target in diseases such as MS, where T-cell activity plays a central role.
Highlights
Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system (CNS) that leads to demyelination and neurodegeneration of gray and white matter [1,2,3]
Lymphocyte populations did not differ between mice from different genotypes (Figure S2N in Supplementary Material), while CD3+ cells and single positive (SP) cells (Figures S2O–Q in Supplementary Material, respectively) were found significantly reduced in RhoAfl/flLckCre+ mice compared with RhoAfl/+LckCre+ and RhoAfl/flLckCre− mice, suggesting that other lymphocytes such as B-cells and NK cells compensated for the lack of T-cells in spleen
RhoA signaling has been reported to be important for T-cell activation in vivo and in various T-cell migration in vitro models [14], the direct impact of RhoA on T-cell’s capacity to cross blood–brain barrier (BBB) and induce disease in the CNS has not been established
Summary
Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system (CNS) that leads to demyelination and neurodegeneration of gray and white matter [1,2,3]. Depletion of lymphocytes after treatment with the anti-CD52 antibody Alemtuzumab dramatically reduced lymphocyte numbers in peripheral blood in RRMS patients, thereby stopping the inflammatory and autoimmune process from causing further CNS damage, resulting in decreased relapse rates [12, 13].
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