LFA-1 Controls Th1 and Th17 Motility Behavior in the Inflamed Central Nervous System

Abstract

Leukocyte trafficking is a key event during autoimmune and inflammatory responses. The subarachnoid space (SAS) and cerebrospinal fluid are major routes for the migration of encephalitogenic T cells into the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis, and are sites of T cell activation before the invasion of CNS parenchyma. In particular, autoreactive Th1 and Th17 cell trafficking and reactivation in the CNS are required for the pathogenesis of EAE. However, the molecular mechanisms controlling T cell dynamics during EAE are unclear. We used two-photon laser microscopy to show that autoreactive Th1 and Th17 cells display distinct motility behavior within the SAS in the spinal cords of mice immunized with the myelin oligodendrocyte glycoprotein peptide MOG35−55. Th1 cells showed a strong directional bias at the disease peak, moving in a straight line and covering long distances, whereas Th17 cells exhibited more constrained motility. The dynamics of both Th1 and Th17 cells were strongly affected by blocking the integrin LFA-1, which interfered with the deformability and biomechanics of Th1 but not Th17 cells. The intrathecal injection of a blocking anti-LFA-1 antibody at the onset of disease significantly inhibited EAE progression and also strongly reduced neuro-inflammation in the immunized mice. Our results show that LFA-1 plays a pivotal role in T cell motility during EAE and suggest that interfering with the molecular mechanisms controlling T cell motility can help to reduce the pathogenic potential of autoreactive lymphocytes.

Regulatory T cells suppress Th17 cell Ca 2+ signaling in the spinal cord during murine autoimmune neuroinflammation

“…The rapid and apparently random local movements of Th17 cells we observe point to a capacity to spread rapidly through CNS tissue while promoting repeated local pathogenic interactions. Similar random-walk motility patterns may allow Th1 or Th17 cells to efficiently detect and mount rapid responses to bacterial and fungal infections (25,51,52). During the chronic phase of EAE, when tail paralysis and hind limb weakness persist, Th17 cells remain predominantly in the lumbar region although their overall number decreases.…”

Functional characteristics of Th1, Th17, and ex-Th17 cells in EAE revealed by intravital two-photon microscopy

“…These parameters are indicative of an increased cell-cell contact and higher pathogenicity [ 52 ]. Previous reports on Th1 and Th17 motility within the CNS showing a different behavior of the cell types have used a different EAE paradigm and monitored cells in the spinal cord close to blood vessels and are therefore not comparable to our experimental setup [ 62 ]. Our results, however, contribute to previous reports claiming ex-Th17 cells unite various detrimental properties highlighting their role for pathogenicity in autoimmunity [ 26 ].…”

Paracellular and Transcellular Leukocytes Diapedesis Are Divergent but Interconnected Evolutionary Events

“…However, other protein-protein interactions could also be contributing to forming these resistive forces. This hypothesis is further supported by the observation that knocking out the lymphocytes Llfa1 gene which is responsible for the interaction with the endothelial cells during the first phase of transmigration resulted in deformations and changing the biomechanical aspects of Th1, including effects on their filopodia and lamellipodia, but not Th17 [ 69 ]. We postulate that single cell RNA-seq analysis could shed more light on CD4+ T cells heterogeneous interactions with the endothelial cells of the BBB [ 70 ].…”

“…CD4+ T cells’ migration and movement are dependent on the cell’s desire to achieve the lowest strain energy state possible [ 67 , 68 ]. Achieving the lowest strain energy state is done by investigating the environment through its parts (filopodia and lamellipodia) to identify the lowest mechanical resistance to the cellular movement [ 69 ]. Due to the difference in nature of the cellular construction between paracellular and transcellular routes, the resistance forces exerted on migrating lymphocytes are different.…”