A TLR/CD44 axis regulates T cell trafficking in experimental and human multiple sclerosis

Summary In the pathogenesis of autoimmune disorders, the modulation of leukocytes′ trafficking plays a central role, still poorly understood. Here, we focused on the effect of TLR2 ligands in trafficking of T helper cells through reshuffling of CD44 isoforms repertoire. Concurrently, strain background and TLR2 haplotype affected Wnt/β-catenin signaling pathway and expression of splicing factors. During EAE, mCD44v9-v10 was specifically enriched in the forebrain and showed an increased ability to bind stably to osteopontin. Similarly, we observed that hCD44v7 was highly enriched in cells of cerebrospinal fluid from MS patients with active lesions. Moreover, TLRs engagement modulated the composition of CD44 variants also in human T helper cells, supporting the hypothesis that pathogens or commensals, through TLRs, in turn modulate the repertoire of CD44 isoforms, thereby controlling the distribution of lesions in the CNS. The interference with this mechanism(s) represents a potential tool for prevention and treatment of autoimmune relapses and exacerbations.
Graphical abstract Host-Pathogen interaction modulating T cell trafficking and tissue infiltration through CD44 variants (CD44v). Circulating T cells through lymphoid and non-lymphoid organs, regulate homeostasis of immune system. The environment could lead an imbalance, also acting on the ability of T cells to move. The expression of certain CD44 isoforms can explain the ability of T cells to infiltrate into the CNS of patients affected by multiple sclerosis, crossing the blood brain barrier. This effect seems to be associated with microbial products, able to modulate CD44 splicing on T cells, that regulate their ability to move (Vestweber, 2015). Created with Biorender.com.
Highlights • Environment and genetic are both involved in the regulation of T cell motility • Pathogens and commensals impact on T cell trafficking through a TLRs/CD44v axis • Regulation of CD44 isoforms by TLRs is a new pathogenetic mechanism of autoimmunity • Modulation of CD44 isoform can be a new target for therapy of multiple sclerosis
Molecular biology; Immunology; Cell biology