The role of galectin-8 in ocular immunity and autoimmunity.
have emerged as potent immunoregulatory molecules that control chronic inflammation
through distinct mechanisms. Galectin-8 (Gal-8), a tandem-repeat type galectin with
unique preference for α2,3-sialylated glycans, is ubiquitously expressed, but
little is known about its role in T cell differentiation. Here, we report that Gal-8
promotes the polyclonal differentiation of p... read morerimary mouse Treg cells in vitro. We further
show that Gal-8 also facilitates antigen-specific differentiation of regulatory T (Treg)
cells, and that Treg cells polarized in the presence of Gal-8 express the inhibitory
coreceptor cytotoxic T lymphocyte antigen-4 (CTLA-4), produce IL-10 at a higher
frequency than control Treg cells, and efficiently inhibit proliferation of activated T
cells in vitro. Investigation of the mechanism by which Gal-8 promotes Treg conversion
also revealed that Gal-8 activates TGFβ signaling and promotes sustained IL-2R
signaling. Taken together, these data suggest that Gal-8 promotes the differentiation of
highly suppressive Treg cells, which has implications for the treatment of inflammatory
and autoimmune diseases. Most importantly, we report that treatment with Gal-8 reduces
retinal pathology and prevents photoreceptor cell damage in a murine model of
experimental autoimmune uveitis. Gal-8 treatment increased the number of Treg in both
the draining lymph node (dLN) and the inflamed retina. Moreover, a greater percentage of
Treg cells in the dLN and retina of Gal-8 treated animals expressed CTLA-4, IL-10, and
the tissue-homing integrin CD103. Treg cells in the retina of Gal-8-treated mice were
primarily inducible Treg cells that lack the expression of neuropilin-1. In addition,
Gal-8 treatment blunted production of inflammatory cytokines by retinal T helper type
(TH) 1 and TH17 cells. The effect of Gal-8 on T cell differentiation and/or function was
specific for tissues undergoing an active immune response, as Gal-8 treatment had no
effect on T cell populations in the spleen. Given the need for rational therapies for
managing human uveitis, Gal-8 emerges as an attractive therapeutic candidate not only
for treating retinal autoimmune diseases, but also for other TH1- and TH17-mediated
Thesis (Ph.D.)--Tufts University, 2015.
Submitted to the Dept. of Immunology.
Advisors: Noorjahan Panjwani, and Peter Brodeur.
Committee: Miguel Stadecker, Pilar Alcaide, and Andrew Taylor.
Keywords: Immunology, and Ophthalmology.read less