Galectin-1 Tunes TCR Binding and Signal Transduction to Regulate CD8 Burst Size

Abstract

T cell burst size is regulated by the duration of TCR engagement and balanced control of Ag-induced activation, expansion, and apoptosis. We found that galectin-1-deficient CD8 T cells undergo greater cell division in response to TCR stimulation, with fewer dividing cells undergoing apoptosis. TCR-induced ERK signaling was sustained in activated galectin-1-deficient CD8 T cells and antagonized by recombinant galectin-1, indicating galectin-1 modulates TCR feed-forward/feedback loops involved in signal discrimination and procession. Furthermore, recombinant galectin-1 antagonized binding of agonist tetramers to the TCR on activated OT-1 T cells. Finally, galectin-1 produced by activated Ag-specific CD8 T cells negatively regulated burst size and TCR avidity in vivo. Therefore, galectin-1, inducibly expressed by activated CD8 T cells, functions as an autocrine negative regulator of peripheral CD8 T cell TCR binding, signal transduction, and burst size. Together with recent findings demonstrating that gal-1 promotes binding of agonist tetramers to the TCR of OT-1 thymocytes, these studies identify galectin-1 as a tuner of TCR binding, signaling, and functional fate determination that can differentially specify outcome, depending on the developmental and activation stage of the T cell.

N- and O-Glycans Modulate Galectin-1 Binding, CD45 Signaling, and T Cell Death

“…Specific CD45 isoforms contribute to the intensity of TCR signals (55,59). Additionally, galectin-1 regulates the threshold of TCR signaling and tunes thymocyte selection (4,60). Together, these findings demonstrate that the presentation of specific N-and O-glycans by CD45 on thymocytes, influenced both by CD45 isoform usage and regulated glycosyltransferase expression, is critical for proper thymocyte development and selection involving galectin-1.…”

“…Both positive and negative thymocyte selection are regulated by galectin-1, an endogenous lectin expressed by thymic epithelial cells (2,3). Galectin-1 binding to developing thymocytes can influence the strength of T cell receptor (TCR) 2 signaling, an important factor in determining if a T cell can properly recognize antigen (3,4). Galectin-1 can also directly induce apoptosis of specific thymocyte subsets, as well as activated peripheral T cells (5)(6)(7)(8)(9).…”

“…Galectin-1 can also directly induce apoptosis of specific thymocyte subsets, as well as activated peripheral T cells (5)(6)(7)(8)(9). Galectin-1 knock-out mice have aberrant thymocyte selection, leading to an altered T cell repertoire (3), as well as an altered mature T cell response in the periphery (4). Galectin-1 preferentially binds to lactosamine sequences (Gal␤1,4GlcNAc) on both N-and O-glycans, and thus can bind to a wide variety of T cell surface glycoproteins that bear these glycans.…”

Knockdown of Core 1 Beta 1, 3-galactosyltransferase Prolongs Skin Allograft Survival with Induction of Galectin-1 Secretion and Suppression of CD8+T Cells

“…In contrast, lowGal-1 but not highGal-1 is dependent on the presence of p56lck and ZAP70 and activates caspase cascade [34]. It is also reported that CD7 delivers a pro-apoptotic signal during galectin-1-induced T cell death, specifically modulates TCR signals, and inhibit IL-2 production and proliferation [38][39][40]. The presence of low concentration (20 ng/ml) of gal-1 had different consequence to the cells at various maturation stages [41].…”

Galectin-1 and Its Role in Development of Innate and Adaptive Immunity

“…Впер-вые название галектины было введено в 1994 году. В данное семейство белков объединены β-галактозид-связывающие лектины с консер-вативной гомологичной аминокислотной по-следовательностью углевод-распознающего до-мена (CRD, carbohydrate-recognition domain) и обладающие высоким сродством к поли-N-ацетиллактозамин-богатым гликоконъюга-там [30].…”