Dynamics of Regulatory T Cell-Mediated Control of Antigen Responses and Autoimmune Neuroinflammation

Rationale: Despite the indispensable contribution of regulatory T cells (Tregs) for maintenance of immune homeostasis and prevention of autoimmune disease, little is known about their cellular dynamics during suppression of T cell priming and neuroinflammation in experimental models of multiple sclerosis.  

Methods: Transgenic mice carrying florescent proteins in a cell-specific manner allow simultaneous imaging of complex interactions. Using two-photon microscopy, we characterize the behavior of Tregs during antigen-specific T cell priming in lymph node and, using the myelin oligodendrocyte glycoprotein (MOG) model of experimental autoimmune encephalomyelitis (EAE), during autoimmune demyelination in spinal cord. 

Results: Under steady-state conditions, Tregs exist as two non-overlapping populations that explore the T-zone and the B cell follicle. In the T-zone, Tregs migrate more rapidly than conventional T cells (Tconv) and interact with both resident dendritic cells (DC) and Tconv. During an antigen-specific immune response, Tregs interact with antigen-induced DC:Tconv clusters. Blocking CTLA-4 reduces Treg-Tconv interaction times, increases the volume of DC:Tconv clusters, and subsequently enhances Tconv proliferation in vivo. In the EAE model, Th17 cells mediate neuroinflammation and Tregs promote remission. During EAE, Tregs home to sites of ectopic lymphoid structures in spinal cord where they actively interact directly with Th17 cells engaging APCs.

Conclusions: Our results demonstrate a role of altered cellular choreography, mediated by Tregs through CTLA4-based interactions, to reduce Tconv:DC clustering during helper T cell priming. Our study of cellular competition-based immunoregulation provides the first visualization of Treg suppression of Tconv cell priming and of neuroinflammatory cell interactions in spinal cord during EAE.