Mesenchymal stromal cells affect CD8 naïve to memory subsets polarization by down-modulating IL12Rβ1 and IL2Rα signaling pathways

Abstract

AbstractAdaptive immunity is typified by specificity and memory. Immune memory protects from subsequent infection and relies on functional, fully activated, T lymphocytes. Mesenchymal stromal cells (MSC) have been investigated for their potential therapeutic applications in a variety of diseases in which a dysregulated immune response plays a central role in pathogenesis or progression. Notably, for adaptive immunity, MSC can reduce the activation and cytotoxic activity of CD8+T lymphocytes as well as the polarization of CD4+T lymphocytes toward inflammatory subsets while favoring polarization toward the T regulatory subset. Although MSC have been widely reported to impact CD4 T cell proliferation and polarization, how MSC affect T-cell commitment toward memory subsets is still not known. Here, we report for the first time that MSC isolated from the amniotic membrane of human term placenta (hAMSC) determine T cell fate. We show that hAMSC influence naïve CD8+T cell activation and differentiation by downregulating mTOR pathway activation and modulating the expression of Tbet and Eomes, master regulators of the commitment of naïve CD8+T cells toward memory precursor effector cells (MPECs). This effect can be partly attribute to the ability of hAMSC to reduce the phosphorylation of STAT4 and STAT5, two transcriptional factors downstream IL-12Rβ1 and IL-2Rα receptors. Our results unravel a novel feature of MSC, offering new mechanistic insights into the effects of MSC in the treatment of diseases characterized by an altered activation of memory subsets, such as autoimmune diseases and graft versus host disease.