Galectin-9-CD44 Interaction Enhances Stability and Function of Adaptive Regulatory T Cells

Abstract

The β-galactoside-binding protein galectin-9 is critical in regulating the immune response, but the mechanism by which it functions remains unclear. We have demonstrated that galectin-9 is highly expressed by induced regulatory T cells (iTreg) and was crucial for the generation and function of iTreg cells but not natural regulatory T (nTreg) cells. Galectin-9 expression within iTreg cells was driven by the transcription factor Smad3, forming a feed-forward loop, which further promoted Foxp3 expression. Galectin-9 increased iTreg cell stability and function by directly binding to its receptor CD44, which formed a complex with transforming growth factor-β (TGF-β) receptor I (TGF-βRI), and activated Smad3. Galectin-9 signaling was further found to regulate iTreg cell induction by dominantly acting through the CNS1 region of Foxp3 locus. Our data suggest that exogenous galectin-9, in addition to being an effector molecule for Treg cells, acts synergistically with TGF-β to enforce iTreg cell differentiation and maintenance.

Impact of Exogenous Galectin-9 on Human T Cells

“…Then the question arises of what makes a connection between gal-9 binding to the plasma membrane and changes of the TCR-CD3 complex. As mentioned previously, several surface proteins distinct from Tim-3 can bind gal-9 and have been proposed as candidate membrane receptors, especially CD44, CD137, and the enzyme disulfide isomerase (18,(23)(24)(25). Gal-9 can also bind surface glycolipids, for example the Forssman glycolipid (52).…”

“…However, in the past few years, this point has been the subject of controversies (20 -22). There is strong evidence that gal-9 is an agonist of Tim-3 in some circumstances, but it is obvious that gal-9 has other membrane receptors, for example the enzyme "disulfide isomerase," the CD137, or CD44 molecule (18,(23)(24)(25). In brief, gal-9 is likely to have several types of membrane receptors and to interact with various combinations of receptors depending on the type of target cells.…”

Towards molecular mechanisms regulating the expression of galectins in cancer cells under microenvironmental stress conditions

“…Moreover, individual factors mimicking or associated with inflammatory stress, such as LPS, IFN-c, TNF, and IL-1b, are powerful stimuli for galectin-9 expression in a variety of cells, including vascular endothelial cells [133,134], monocytes [135], macrophages [136], fibroblasts [137], multipotent mesenchymal stromal cells [138], and astrocytes [139,140]. A variety of transcription factors and related signaling pathways have been reported to be essential for the upregulation of galectin-9, including a redox-sensitive JNK/c-Jun signaling pathway in astrocytes [140], the phosphorylation of STAT-1 in HUVEC cells [141], and Smad3 in regulatory T cells [142]. Although it remains unclear how galectin-9 collaborates with other galectins, the administration of the recombinant galectin-9 seems to be a very promising strategy for treating immune and cancer diseases [131].…”

A review of the importance of immune responses in luminal B breast cancer

“…PD-1/PD-L1 interactions are also likely to occur in tumor- In pre-clinical development [54][55][56][57][58][59][60][61][62] draining lymph nodes that have not yet been extensively assessed in many cancers, including BC subtypes. Moreover, a threshold level has not been set as inclusion criteria for treatment with PD-1 or PD-L1 in any cancer, and even low levels as reported in luminal B BC might be sufficient justification for a clinical trial.…”

“…59 Gal-9 expression by endothelial cells enables cytolysis of immune cells before they infiltrate tumors. 60 Moreover, Gal-9 promotes Treg proliferation 61 and tumor metastasis by facilitating tumorendothelial cell interactions 58 . The role of members of the galectin family including Gal-9 in BC subtypes is unclear although, its expression on stromal cells has been reported in TNBC and HER-2 C subtypes.…”