Intracellular Galectin-3 Is Essential for OX40-Mediated Memory CD8+ T Cell Development

Abstract

CD8+ T cells are critical mediators of adaptive immunity, and enhancing their function can promote robust responses against invading pathogens and neoplastic cells. In addition to TCR stimulation, the provision of costimulation through ligation of TNFR family members, such as OX40 (CD134), provides essential signals driving T cell differentiation, survival, and memory in part through enhanced IL-2/IL-2R signaling. Interestingly, TCR stimulation in the presence of IL-2 upregulates intracellular expression of the β-galactoside binding protein, Galectin-3 (Gal-3). Gal-3 has been shown to regulate Th1/Th2 polarization of CD4+ T cells; however, the extent to which Gal-3 regulates the OX40/IL-2 signaling axis and CD8+ T cell proliferation, effector function, and/or survival is unknown. In this study, we demonstrate that murine Gal-3–deficient CD8+ T cells exhibited no defects in early (36 h) activation or proliferation following TCR stimulation. In contrast, Gal-3−/− CD8+ T cells exhibited decreased survival and a reduced capacity to develop into memory cells following stimulation with cognate Ag plus agonist anti-OX40 mAb or IL-2 in vivo. Decreased survival of Gal-3−/− T cells was associated with increased apoptosis and occurred in a cell-intrinsic manner. Together, these data implicate intracellular Gal-3 as a critical mediator of OX40-mediated CD8+ T cell survival and memory formation following Ag exposure.

The role of galectins in immunity and infection

“…In addition, intracellular galectin-3 can inhibit T cell apoptosis through interactions with the anti-apoptotic protein BCL-2 (refs. 49 , 50 ). c , Galectins have also been shown to regulate B cell differentiation through extracellular and possibly intracellular processes.…”

“…This activity does not appear to be limited to galectin-1, as similar in vitro studies suggested that extracellular galectin-2, -3, -8 and -9 may exert an immunosuppressive function by directly inducing apoptosis in T cells 45 – 48 . Additional studies indicate that intracellular galectin-3 can also inhibit T cell apoptosis in a cell-intrinsic manner 49 , 50 and galectin-3 was shown to have sequence homology with and bind to the anti-apoptosis protein BCL-2 (ref. 50 ).…”

Medawar’s PostEra: Galectins Emerged as Key Players During Fetal-Maternal Glycoimmune Adaptation

“…Among other mechanisms, gal-3 modulates adaptive immunity by enhancing tolerogenic (i.e., regulatory) IDO-expressing DC that support Treg expansion ( 75 ), acting extracellularly to inhibit TCR signaling at the immunological synapse ( 76 ) and by interfering with co-inhibitory receptor signaling [i.e., PD-1 and LAG-3, ( 77 )]. Intracellularly, gal-3 appears to be critical for supporting OX-40 mediated development of memory CD8+ T cells following antigen exposure ( 78 ). Additionally, under sustained tissue damage, gal-3 can promote the transition to chronic inflammation, quenching T cell responses ( 64 , 79 ) and facilitating the walling off of tissue injury with fibrogenesis and organ scarring ( 80 ).…”

Unraveling How Tumor-Derived Galectins Contribute to Anti-Cancer Immunity Failure

“…Subject to the surrounding microenvironment, endogenous galectin-3 is upregulated in T cells early upon activation and skews their differentiation program. Indeed, galectin-3 deficiency promotes immune responses that favor effectors and effector memory T cells to the detriment of the generation of central memory T cells [ 85 , 206 ]. Furthermore, it was described that the survival of recently activated T cells might be affected by galectin-3.…”

“…However, similarly to what was discussed on galectin-1, it is unlikely that tumor-derived circulating galectin-3 reaches the concentrations required to reveal its pro-apoptotic properties in the tumor-draining lymph nodes in cancer patients. It is also important to note that during activation, lymphocytes upregulate intracellular galectin-3 [ 206 , 207 ], which protects T cells from apoptosis [ 147 , 206 ]. Thus, the role of galectin-3 on the survival of newly activated lymphocytes in the lymph nodes is complex, and its real pathologic relevance remains controversial.…”