The role of Galectin-9 on T cell trafficking in inflammation

Abo Mansour, Adel (2023). The role of Galectin-9 on T cell trafficking in inflammation. University of Birmingham. Ph.D.

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Abstract

T cell trafficking is a fundamental process required for a range of homeostatic functions but also critical for effective elimination of invading pathogens and inflammation resolution. Aberrant T cell trafficking is associated with the onset of chronic inflammation which is a hallmark of a range of conditions including rheumatoid arthritis and chronic transplant rejection. Galectins are a family of β-galactoside binding proteins with a variety of critical cellular functions, however, to date, very little is known about their role in the underlying pathways involved in the recruitment of T cells. The aim of this thesis was to investigate whether Galectin-9 (Gal-9) modulates the recruitment of different T lymphocyte subsets.

Results presented in this thesis indicate that Gal-9 supports both CD4+ and CD8+ T cell adhesion and transmigration in a glycan dependent manner, inducing L-selectin shedding and upregulation of LFA-1 and CXCR4 expression. Additionally, when immobilized, Gal-9 promotes capture and firm adhesion of T cells under flow, in a glycan and integrin-dependent manner. Using an in vivo model, dorsal air pouch, we found that Gal-9 deficient mice display impaired leukocyte trafficking, with a reduction in pro-inflammatory cytokines/chemokines generated locally. Furthermore, we also demonstrate that Gal-9 inhibits the chemotactic function of CXCL12 through direct binding. In a model of acute inflammation, gouty induced arthritis, we found that therapeutic application with exogenous Gal-9 supported inflammation resolution, with a reduction in innate immune cell recruitment and pro-inflammatory mediator production. We also found that T regulatory (Treg) levels were maintained in mice treated with exogenous Gal-9 and in vitro Gal-9 treatment of human naïve CD4+ T cells supported T cell expansion and differentiation towards a Treg phenotype.

In conclusion, our study characterises, for the first time, the capture, adhesion, and migratory behaviour of CD4+ and CD8+ T cells to immobilised /endothelial presented Gal-9, under static, physiological flow conditions and in acute inflammatory settings in vivo. We also demonstrate the differential binding characteristics of Gal-9 to T cell subtypes, which could be of potential therapeutic significance, particularly in the treatment of immune-mediated inflammatory diseases, given Gal-9 ability to promote apoptosis in pathogenic T cell subsets and support Treg expansion.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):