Spatiotemporal Dynamics of Immune Cells in the Spinal Cord During CNS Autoimmunity

Our immune system is a dynamic network of cells and molecules that constantly protects us from pathogens. During an immune response, information about the pathogen is quickly relayed to the nearest lymphoid organs. Fast-moving immune cells (lymphocytes) constantly scan lymphoid organs for specific signals displayed on antigen-presenting cells (APC). Once lymphocytes encounter their antigens, they proliferate, differentiate into effector cells, and migrate to target tissues to execute effector functions (e.g., clear pathogens). These steps involve complex cell migration, cell-cell interactions, and signaling events that are exquisitely regulated to ensure targeted clearance of pathogens while limiting fatal autoimmunity. Misfiring immune cells against self-tissues can lead to more than 80 autoimmune disorders, including Multiple Sclerosis (MS), in which immune cells attack the protective myelin sheath of the neurons in the central nervous system (CNS). We aim to understand better how immune cells couple cell migration to functions in target tissues.

Effector T (Teff) cells potentiate CNS autoimmunity, whereas regulatory T (Treg) cells limit autoimmunity. Using a combination of multiphoton imaging and transgenic mice in an MS-like disease model called experimental autoimmune encephalomyelitis, we provide new insights into the cellular dynamics of Teffs, Tregs, and APCs in the spinal cord. Despite similar cell speeds, Teff and Treg cells follow divergent motility patterns. Teff cells actively migrate to spread across the CNS. In contrast, Tregs remain organized as discrete clusters. Tregs exhibit an unusual repetitive scanning behavior, allowing rapidly motile Tregs to re-engage their targets constantly. We postulate that this motility behavior of Tregs limits Teff cell activation by destabilizing Teff cell interactions with local APCs. We demonstrate that the arrival of Tregs in the CNS coincides with diminished activation of Teff cells and a partial recovery from disease; depletion of Treg cells quadruples the number of Teff cells within days. We provide evidence that Treg cells interfere with proximal signaling in Teff cells. Altogether, our results provide new insights into the spatial organization and cellular interactions of immune cells that play a critical role in CNS autoimmunity.