Galectin-1: a key effector of regulation mediated by CD4+CD25+ T cells

Abstract

The naturally occurring population of dedicated regulatory T cells that coexpress CD4 and CD25 is known to play a key role in the maintenance of peripheral T-cell tolerance; however, their mechanism of action has remained obscure. Here we report that a member of the family of ␤-galactoside-binding proteins, galectin-1, is overexpressed in regulatory T cells, and that expression is increased after activation. Most importantly, blockade of galectin-1 binding significantly reduced the inhibitory effects of human and mouse CD4 ؉ CD25 ؉ T cells. Reduced regulatory activity was observed in CD4 ؉ CD25 ؉ T cells obtained from galectin-1-homozygous null mutant mice. These results suggest that galectin-1 is a key effector of the regulation mediated by these cells. IntroductionMore than 10 years ago, T lymphocytes, which constitutively coexpress CD4 and CD25 and represent approximately 5% of murine peripheral T cells, were shown to play a key role in the prevention of autoimmunity. 1,2 Similar cells have since been characterized in human peripheral blood. 3,4 These cells differ from recently activated CD4 ϩ T cells expressing CD25 because of their low-level expression of surface markers of activation such as CD69. In contrast to CD4 ϩ CD25 Ϫ T cells, CD4 ϩ CD25 ϩ T cells are hyporesponsive in vitro to polyclonal T-cell-receptor (TCR) stimuli. After activation they do not produce interleukin-2 (IL-2), IL-4, interferon (IFN)-␥, or IL-10, and their anergic state can be partially restored by IL-2. The mechanism of regulation appears to involve the inhibition of transcription of cytokine genes, most notably IL-2 and IFN-␥, leading to reduced proliferation. 5,6 In mouse models, Papiernik et al have demonstrated that CD4 ϩ CD25 ϩ T cells originate in the thymus, where they are induced to express CD25 at the CD4 single-positive stage, before migration to the periphery. 7 Although the generation of CD4 ϩ CD25 ϩ T cells during T-cell differentiation has not yet been fully characterized, it appears that the relatively high affinity of these cells for self-antigens falls between that required for positive and negative selection. 8 The importance of naturally occurring CD4 ϩ CD25 ϩ regulatory T (Treg) cells for maintenance of peripheral T-cell tolerance is well established, but their mechanisms of action remain elusive. Treg cells express high levels of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), which, it has been suggested, may act by sequestering B7 family molecules and inhibiting the costimulation of neighboring T cells. 9 However, since CD4 ϩ CD25 ϩ Treg cells effect suppression in the absence of B7-expressing antigenpresenting cells, this cannot be a universal explanation. 3 Cellsurface-transforming growth factor ␤-1 (TGF-␤1) has also been implicated, although this has not been reproduced. 10,11 It has recently been reported that Lag-3 contributes to the function of naturally occurring regulatory cells, but the reversal of suppression achieved by Lag-3 blockade was only modest. 5,6,12 Although cytokines such as IL-10 a...

The AP1-dependent secretion of galectin-1 by Reed–Sternberg cells fosters immune privilege in classical Hodgkin lymphoma

“…In fact, T reg cells have been reported to exhibit increased ␣2,6 sialylation (compared with effector T cells) (31); this selective sialylation might interfere with Gal1 binding and cell death (32). This hypothesis is further supported by recent studies demonstrating that T reg cells overexpress Gal1 and remain resistant to Gal1-mediated apoptosis (33).…”

Functions of cell surface galectin-glycoprotein lattices

“…We found that treatment with recombinant galectin-1 in the efferent phase of autoimmune ocular inflammation results in increased IL-10 and TGF-β production and expansion of regulatory T cells in vivo [43]. Interestingly, recent studies demonstrated that galectin-1 and -10 are overexpressed in regulatory T cells, and are critical for the suppressive activity of these cells [49,50]. Further studies are needed to establish a role of galectin-carbohydrate lattices at synapse formation between regulatory and effector T cells.…”

T cell apoptosis at the maternal–fetal interface in early human pregnancy, involvement of galectin-1

“…Interestingly, CD4 ϩ CD25 ϩ regulatory T cells have been shown to mediate their suppressive activity through gal1 (40).…”