Manipulating Antigenic Ligand Strength to Selectively Target Myelin-Reactive CD4+ T Cells in EAE

Abstract

The development of antigen-specific therapies for the selective tolerization of autoreactive T cells remains the Holy Grail for the treatment of T-cell-mediated autoimmune diseases such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). This quest remains elusive, however, as the numerous antigen-specific strategies targeting myelin-specific T cells over the years have failed to result in clinical success. In this review, we revisit the antigenbased therapies used in the treatment of myelin-specific CD4+ T cells in the context of the functional avidity and the strength of signal of the encephalitogenic CD4+ T cell repertoire. In light of differences in activation thresholds, we propose that autoreactive T cells are not all equal, and therefore tolerance induction strategies must incorporate ligand strength in order to be successful in treating EAE and ultimately the human disease MS.

Protection of Tregs, Suppression of Th1 and Th17 Cells, and Amelioration of Experimental Allergic Encephalomyelitis by a Physically-Modified Saline

“…Once there, these cells initiate, promote, and aggravate multifaceted inflammatory and degenerative insults ultimately leading to demyelination and axonal injury. There are many hypotheses to explain how auto-reactive T cells might be activated, including microbial, viral infection, and molecular mimicry [30], [32], [33]. However, no consensus has been achieved due to the lack of convincing evidence.…”

Low 2-Dimensional CD4 T Cell Receptor Affinity for Myelin Sets in Motion Delayed Response Kinetics

“…The library of peptides for a specific TCR includes agonists, partial or weak agonists, and antagonists [4]. In the case of CD8+ OT-I T cells, these ligands can span a >1,000 fold range in effective 2D affinity [5].…”

Neuroimmune Pharmacological Control of EAE

“…During clonal selection, only those T cell clones that receive sufficient stimulation by foreign antigenic peptide/major histocompatibility complex complexes are activated and expand. In a far-reaching review, Sabatino et al (2010) have delineated how ligand strength contributes to the degree of T cell activation and how this is dependent on the extent and quality of T cell signaling. They have proposed that autoreactive T cells are not all equal, and therefore tolerance induction strategies must incorporate ligand strength in order to be successful in treating EAE and ultimately the human disease MS.…”