Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway

Abstract

Bone marrow mesenchymal progenitor cells (BMSC) are used for regenerating tissues of mesodermal origin, as well as tissues of different embryological derivation. Experimental evidence shows that BMSC are able to suppress the activation of the immune response by mechanisms that are still not completely understood. Thus far, in vitro studies carried using human or mouse cells indicate that autologous or allogeneic BMSC strongly suppress proliferation of T lymphocytes, triggered by cellular stimuli, nonspecific mitogenic stimuli, or antigenic peptides. Using cell proliferation and blocking assays, we demonstrated that BMSC inhibited the activation of murine splenocytes, T, and B lymphocytes. Direct contact of BMSC and target cells in a cognate fashion determined the inhibition of cell proliferation via engagement of the inhibitory molecule programmed death 1 (PD-1) to its ligands PD-L1 and PD-L2, leading the target cells to modulate the expression of different cytokine receptors and transduction molecules for cytokine signaling. Soluble factors present on supernatants of BMSC cultures were effective in suppressing proliferation of B cells to a mitogenic stimulus. Taken together, these results highlight the complexity of the role of BMSC in regulating the immune response, asserting the possibility of their therapeutic application in transplantation and autoimmune diseases.

Immunoregulatory function of mesenchymal stem cells

“…In mouse experiments, B lymphocytes were enriched from splenocyte suspensions and activated in vitro using T cell-dependent stimuli. In this context, Glennie et al used an anti-CD40 mAb and IL-4 [45], while Augello et al stimulated splenic B cells with pokeweed mitogen [49]. Both studies reached the same conclusion, i.e.…”

“…Inhibition of T cell proliferation resulted in the decreased production of effector Th1 cytokines [16,42,46]; however, the expression of activation markers in T cells that have been cultured with MSC remains a controversial issue [39,43,45,47]. Inhibition of T cell proliferation by MSC appears to be subsequent both to cell-to-cell interaction and to the release of soluble factors, and it is conceivable that discrepant findings reported in the literature reflect differences in the experimental conditions used [13,14,16,48,49]. TGF-b1 and HGF [13], indoleamine 2,3-dioxygenase (IDO) [50] and prostaglandin E2 (PGE-2) [46] represent MSC-derived molecules that have been proposed to exert immunomodulatory activity on T cell responses.…”

Immune Regulatory Properties of CD117pos Amniotic Fluid Stem Cells Vary According to Gestational Age

“…Finally, we assessed the expression of two immunosuppressive molecules, CD274 (PD-L1) and CD200 (OX-2), which are involved in the modulation of T cell proliferation [25][26][27]. CD274 was expressed by all AFS cells at resting conditions, but variably upregulated by inflammatory priming (4.04-fold in first trimester, 3.06-fold in second trimester, and 3.2-fold in third trimester, respectively) (Fig.…”

Stromal cells–are they really useful for GVHD?

“…61 Activated MSCs can modulate adaptive immune cells through contact-dependent mechanisms. These include activation of the PD-1 pathway, 62 Fas-mediated T-cell apoptosis, 63 engagement of …”