Final Report Summary - RA AND GD T CELLS (The effect of retinoic acid on the fate of γδ T cells)
Retinoic acid, the active metabolite of vitamin A, can modulate immune responses. In the steady-state, it can help to maintain tolerance against commensal bacteria through the induction of regulatory T cells that suppress immune responses. By contrast, in inflammatory conditions, retinoic acid can promote effector T cells that mediate inflammation. Here we examined the effect of retinoic acid on γδ T cells, a subpopulation of immune cells that play crucial roles in defending the mucosal surfaces of the body against infection but are also involved in sterile inflammation that can lead to autoimmune diseases. Indeed γδ T cells strongly influence many other immune and non-immune cells, especially through their secretion of specialized proteins called cytokines. Thus they can rapidly switch from a pro-inflammatory to an anti-inflammatory state and vice versa, which strongly impacts the behaviour of the other cell types and therefore the equilibrium of the immune system. γδ T cells also have the capacity to be self-reactive, and therefore can play a pathogenic role in the development of autoimmune diseases, such as psoriasis, multiple sclerosis and rheumatoid arthritis. In this study we found that retinoic acid had a dramatic suppressive effect on the pathogenicity of γδ T cells purified from lymph nodes, spleens and skin of mice. Retinoic acid inhibited the capacity of γδ T cells to differentiate, proliferate and respond to pathogenic stimuli. Furthermore, treatment of mice with retinoic acid delayed onset and significantly reduced the symptoms of diseases in a mouse model of a multiple sclerosis. We found that retinoic acid decreased the frequency and activity of the autoreactive γδ T cells and CD4 helper T cells that infiltrate the central nervous system to cause neuroinflammation, a process that leads to nerve damage and gradual paralysis in multiple sclerosis. Furthermore, depletion of γδ T cells reduced the capacity of immune cells to induce the multiple sclerosis-like disease. Interestingly treatment of this single cell type with retinoic acid was enough to prevent immune cells from transferring diseases to recipient mice. Our findings demonstrate that retinoic acid has powerful anti-inflammatory properties in a model of multiple sclerosis that are mediated by suppressing the pathogenic function of γδ T cells. As γδ T cells play a damaging role in a number of autoimmune diseases, our findings have implications for the treatment of these diseases, but also suggest that simple dietary interventions that involve consumption of vegetable rich in vitamin A may help to re-set the immune imbalance in these debilitating diseases.