Immune contributions to PD pathogenesis. Reactive microgliosis is a prominent feature of neurodegenerative diseases such as PD. Microglia are sensitive to changes in their microenvironment, which include factors released from damaged/dying neurons such as modified and aggregated proteins (i.e., α-synculein found in Lewy bodies). Activated microglia may respond to these factors by secreting proinflammatory factors and ROS/RNS that perpetuate neuronal injury and death. Furthermore, modified α-synuclein (e.g., N-α-synunclein) may drain to the periphery where an adaptive immune response is mounted against these antigens. Although increased numbers of lymphocytes are found in the SN of PD patients’ brains, their exact role is not yet known. However, experimental evidence suggests that effector T-cell (E) responses contribute to microglia activation and accelerate neurodegeneration. Taken together, the innate and adaptive immune responses operative in PD may accelerate neurodegeneration and are an active area of research.

Adaptive immunity for therapeutic gain. Regulatory T cells (T_reg, R) work to control excessive inflammation and may be harnessed to control neuroinflammation in PD and other neurodegenerative diseases. T_reg can modulate microglia and other immune cells away from proinflammatory responses to anti-inflammatory/homeostatic functions. Therefore, strategies aimed at inducing, boosting, or reprogramming T_reg responses (e.g., functional transformation of T_eff [E] to T_reg, increasing nT_reg numbers, or activating T_reg in an antigen-specific manner) show promise as possible disease-modifying therapies. T_reg can modulate immune responses via several mechanisms, including suppressing microglia activation, inducing microglia phenotypic switching (toward anti-inflammatory), killing activated cells (e.g., T_eff and microglia), and inhibition of APC maturation and antigen presentation. All together, T_reg may suppress innate and adaptive proinflammatory, neurotoxic immune responses and boost homeostatic, neurotrophic immune responses resulting in slowing of neurodegeneration and allowing repair of damaged neurons. Such strategies may help to slow or halt the progression of PD.