Neuroinflammation: Microglia and T Cells Get Ready to Tango

Abstract

In recent years, many paradigms concerning central nervous system (CNS) immunology have been challenged and shifted, including the discovery of CNS-draining lymphatic vessels, the origin and functional diversity of microglia, the impact of T cells on CNS immunological homeostasis and the role of neuroinflammation in neurodegenerative diseases. In parallel, antigen presentation outside the CNS has revealed the vital role of antigen-presenting cells in maintaining tolerance toward self-proteins, thwarting auto-immunity. Here, we review recent findings that unite these shifted paradigms of microglial functioning, antigen presentation, and CNS-directed T cell activation, focusing on common neurodegenerative diseases. It provides an important update on CNS adaptive immunity, novel targets, and a concept of the microglia T-cell equilibrium.

Keywords: T cells; antigen presentation; central nervous system; inflammation; microglia; tolerance.

Figure 1

Microglia-T cell equilibrium; activated microglia and infiltrating T cells interact during chronic neurodegeneration and shape central nervous system (CNS) immunology and neuropathology. Commonalities of neurodegenerative disease include accumulation of misfolded self-antigen, T cell infiltration, microglial proliferation and activation, and progressive neuronal dysfunction and death. (1) Self-antigens like amyloid β and α-synuclein are accumulating and often aberrantly post-translationally modified. (2) These antigens can drain to lymph nodes outside the CNS and be presented to T cells by resident antigen-presenting cells. (3) CNS-antigen-specific T cells enter the brain through the vasculature and encounter microglia in the brain paranchyma. (4) Microglia express many molecules that recognize and bind neuronal aberrancies (5) like desialylated glycocalyx or complement deposition on neurites, as well as aberrant self-antigens like aggregated amyloid β. At the same time, these receptors induce proliferation and signaling. Inhibitory receptors (represented in blue) are mainly implicated in reducing inflammation, while the activating receptors (represented in red) mainly induce inflammation. As a result, cellular debris and antigen is taken up, processed, and presented on MHC class II, enabling the interaction with infiltrating antigen-specific T cells. In turn, contact-dependent interactions and soluble factors may affect the phenotype of incoming T cells. (6) The microglia-T cell equilibrium ensures limitation of protective adaptive immunity after neuronal damage and prevents auto-immunity toward CNS-derived antigens.