Mesenchymal Stromal Cells Suppress T-Cell-Mediated Delayed-Type Hypersensitivity via ALCAM-CD6 Interaction

Abstract

Mounting evidence suggests mesenchymal stromal cells (MSCs) suppress CD4+ T-cell activation, but whether MSCs directly regulate activation and expansion of allogeneic T cells has not been fully deciphered. Here, we identified that both human and murine MSCs constitutively express ALCAM, a cognate ligand for CD6 receptors on T cells, and investigated its immunomodulatory function using in vivo and in vitro experiments. Our controlled coculture assays demonstrated that ALCAM-CD6 pathway is critical for MSCs to exert its suppressive function on early CD4+CD25− T-cell activation. Moreover, neutralizing ALCAM or CD6 results in the abrogation of MSC-mediated suppression of T-cell expansion. Using a murine model of delayed-type hypersensitivity response to alloantigen, we show that ALCAM-silenced MSCs lose the capacity to suppress the generation of alloreactive IFNγ-secreting T cells. Consequently, MSCs, following ALCAM knockdown, failed to prevent allosensitization and alloreactive T-cell-mediated tissue damage.

Mesenchymal stromal cells protect tissues from Th1 immune responses via IL‐11 secretion

“…Activation markers CD69 (Figure 2A) and CD40L (Figure 2B) were assessed using flow cytometry analysis. Similar to our previous findings, 17 MSCs significantly suppressed CD4 + T cell activation (Figure 2A,B). However, in the presence of IL11‐neutralizing antibodies, suppression of T cell activation was not observed (Figure 2A,B).…”

“…Interestingly, this suppressive effect was not observed following IL11 neutralization, suggesting a significant contribution of IL11 to MSC's immunomodulatory capacity. Our previous reports showed MSC injections reduce the frequencies of Th1 cells 17 ; the current study reveals the underlying mechanisms and demonstrates that MSCs directly inhibit the expansion of T cells, a key step in mounting an effector T cell response, in an IL11‐dependent manner. Moreover, our data demonstrate that IL11 alone is sufficient in suppressing effector function of CD4 + Th1 cells, as shown by a 50% reduction in IFNγ + CD4 + T effector cells in cultures treated with rhIL11 compared to no treatment cultures.…”

“…In the setting of alloimmunity, we and others have demonstrated that MSCs inhibit T cell proliferation and promote regulatory T cell function through a direct cell–cell contact mechanism 26 . Furthermore, we have demonstrated that MSCs suppress APC maturation and reduce the generation of alloreactive IFNγ‐secreting Th1 cells 17,23 ; however, the mechanisms by which MSCs directly regulate the effector function of alloreactive Th1 cells have not been fully characterized. Here, we delineate that MSCs regulate effector T cell function via secreting immunosuppressive cytokine IL11 in the setting of allogeneic T cell‐dependent inflammation and tissue injury.…”

“…Murine MSCs (1.5 × 10 6 ) were seeded in a 75 cm 2 flask at 60%–70% confluency. The cells were treated with IL11‐specific or control short hairpin RNA (shRNA), previously described 17 . Transfection media was removed after overnight incubation, and cells expressing stable shRNA were selected by culturing in the presence of puromycin (5 μg/mL).…”

CD6 and Its Interacting Partners: Newcomers to the Block of Cancer Immunotherapies

“…Regarding tumorigenesis, they included interference of homotypic CD166/ALCAM-CD166/ALCAM interactions needed for optimal proliferation and migration of mouse tumour cells [60] (Figure 2A,B, right-hand side). Whether shCD6 would interfere with the function of other CD166/ALCAM-expressing immunosuppressive cells from the tumour microenvironment (e.g., mesenchymal stromal cells) should be further addressed [72]. In line with previous studies using non-depleting anti-human and mouse CD6 mAbs [30,32,66], available evidence argues against the possibility that shCD6-based anti-tumour strategies would instigate the development of autoimmune side effects.…”