CD4+ T cells mediate cytotoxicity in neurodegenerative diseases

Abstract

Neuroinflammation, characterized by activated microglia and infiltrating T cells, is a prominent pathological feature in neurodegenerative diseases. However, whether this inflammation contributes to neuronal injury or is a late consequence of neuronal injury is unclear. In this issue of the JCI, Brochard et al. report that CD4+ T cells are cytotoxic in a mouse model of Parkinson disease (PD) (see the related article beginning on page 182). Specifically, invading T lymphocytes contributed to neuronal cell death via the Fas/FasL pathway. The results implicate the adaptive immune system in the pathogenesis of Parkinson neurodegeneration and provide a meaningful rationale for immune-based therapies for PD.

Figure 1. Potential role of T cells in modulating microglia-mediated neurotoxicity.

On the left, the presence of Th1 and Th17 cells upregulates (thick lines) the production and release of free radicals from microglia, including NO, superoxide (O₂^–), and hydrogen peroxide (H₂O₂) as well as proinflammatory cytokines such as TNF-α and IL-1β, and downregulates (thin lines) the release of neurotrophic factors such as IGF-1. The result is enhanced neuronal injury, which may trigger the release of increased levels of nitrated/oxidized α-Syn and enhance microglia-mediated neurotoxicity. Tregs can suppress the proinflammatory effects of Th17 cells. On the right, Th2 cells release IL-4, upregulating the release from microglia of neuroprotective IGF-1, downregulating release of free radicals, and resulting in enhanced neuronal protection.