Galectin-9 Regulates The Threshold of B Cell Activation and Autoimmunity

Abstract

Despite the mechanisms of central and peripheral tolerance, the mature B cell compartment contains cells reactive for self-antigen. How these cells are poised not to respond and the mechanisms that restrain B cells responses to low affinity endogenous antigens are not fully understood. Here, we demonstrate a critical role for the glycan-binding protein galectin-9 in setting the threshold of B cell activation and that loss of this regulatory network is sufficient to drive spontaneous autoimmunity. We further demonstrate a critical role for galectin-9 in restraining not only conventional B-2 B cells, but also innate-like B-1a cells. We show that galectin-9 deficient mice have an expanded population of B-1a cells and increased titers of B-1a derived autoantibodies. Mechanistically, we demonstrate that galectin-9 regulates BCR and distinct TLR responses in B-1a, but not B-1b cells, by regulating the interaction between BCR and TLRs with the regulatory molecules CD5 and CD180, respectively. In the absence of galectin-9, B-1a cells are more readily activated and secrete increased titers of autoantibodies that facilitate auto-antigen delivery to the spleen, driving autoimmune responses.

Measuring the co-localization and dynamics of mobile proteins in live cells undergoing signaling responses

“…Fluorophores labeling proteins of interest stochastically transition between emitting and transiently dark states, allowing for the ensemble of molecules to be fully sampled over time. Single and multi-color SMLM has been used to image components of the immune response in a wide variety of contexts [12][13][14][15][16][17][18][19][20][21]. Our own work has largely focused on probing early events in B cell receptor signaling [22][23][24].…”

Galectin-9 signaling drives breast cancer invasion through matrix

“…Galectin-9 belongs to a subset of the 15 mammalian galectins, with two different CRDs in one peptide chain, here termed N-CRD and C-CRD (10). Rigorous investigations on its functions have predominantly been confined to immunological contexts, such as the activation of dendritic cells and their induction of naïve T cell proliferation, a level dependent modulation of activated T cell fate and the regulation of B-cell driven autoimmunity (11)(12)(13) .…”

“…3.76 -3.65 (m, 2H, H-6, H-6'), 3.46 (dd, J = 10.1, 3.1 Hz, 1H, H-3), 3.09 (td, J = 6.9, 4.5 Hz, 2H, CH2), 2.41 (s, 3H, CH3) 13. C NMR (126 MHz, MeOD) δ 167.3, 166.9, 143.7, 142.9, 142.7, 137.0, 134.4, 134.4, 133.5, 132.7, 132.7, 132.1, 131.7, 130.4, 130.4, 127.1, 127.0, 91.3, 91.2, 80.7, 80.6, 73.6, 73.6, 68.9, 68.8, 67.4, 67.3, 67.2, 67.0, 62.4, 59.5, 58.4, 49.6, 33.2, 32.5, 32.0,The compounds 2 and 3 are dissolved in DMSO and diluted in complete medium for experiments.…”