Lymphocyte activation gene-3 (LAG-3) is a CD4-related transmembrane protein expressed by regulatory T cells that binds MHC II on APCs. It is shown in this study that during Treg:DC interactions, LAG-3 engagement with MHC class II inhibits DC activation. MHC II cross-linking by agonistic Abs induces an ITAM-mediated inhibitory signaling pathway, involving FcγRγ and ERK-mediated recruitment of SHP-1 that suppresses dendritic cell maturation and immunostimulatory capacity. These data reveal a novel ITAM-mediated inhibitory signaling pathway in DCs triggered by MHC II engagement of LAG-3, providing a molecular mechanism in which regulatory T cells may suppress via modulating DC function.

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Unilateral weakness of the lower limb is a hallmark of multiple sclerosis (MS) and a significant contributor to the progressive worsening of walking ability. There are currently no effective rehabilitation strategies targeting strength asymmetries and/or gait impairments in people with MS (PwMS). Transcranial direct current stimulation (tDCS) has improved motor outcomes in various populations, but the effect of tDCS on gait in PwMS and the ideal timing window of tDCS application are still unknown. This study investigated the effects of tDCS, either before or during a 6 min walk test (6MWT), on the distance walked and gait characteristics in PwMS. Twelve participants were recruited and randomly assigned into BEFORE or DURING groups (both n = 6). The BEFORE group received stimulation before performing a 6MWT (sham/2 mA, 13 min). The DURING group received stimulation only during a 6MWT (sham/2 mA, 6 min). Stimulation was over the more MS-affected primary motor cortex (M1). Distance walked and gait characteristics of the walk were the primary and secondary outcomes. The results indicated a significant decrease in distance walked in the DURING group (p = 0.026) and a significant increase in gait velocity in the BEFORE group (p = 0.04). These changes were accompanied by trends (p < 0.1) in distance walked, gait velocity, and stride length. Overall, the results of this study suggest that tDCS performed before a 6MWT might be more effective than tDCS during a 6MWT and that a single session of tDCS may not be sufficient to influence gait.Clinical Trial Registration: www.ClinicalTrials.gov, identifier #NCT03757819.

People with Parkinson’s disease (PwPD) often experience gait and balance problems that substantially impact their quality of life. Pharmacological, surgical, and rehabilitative treatments have limited effectiveness and many PwPD continue to experience gait and balance impairment. Transcranial direct current stimulation (tDCS) may represent a viable therapeutic adjunct. The effects of lower intensity tDCS (2 mA) over frontal brain areas, in unilateral and bilateral montages, has previously been explored; however, the effects of lower and higher intensity cerebellar tDCS (2 mA and 4 mA, respectively) on gait and balance has not been investigated. Seven PwPD underwent five cerebellar tDCS conditions (sham, unilateral 2 mA, bilateral 2 mA, unilateral 4 mA, and bilateral 4 mA) for 20 min. After a 10 min rest, gait and balance were tested. The results indicated that the bilateral 4 mA cerebellar tDCS condition had a significantly higher Berg Balance Scale score compared to sham. This study provides preliminary evidence that a single session of tDCS over the cerebellum, using a bilateral configuration at a higher intensity (4 mA), significantly improved balance performance. This intensity and cerebellar configuration warrants future investigation in larger samples and over repeated sessions.