Mesenchymal Stromal Cells Stimulate the Proliferation and IL-22 Production of Group 3 Innate Lymphoid Cells

Abstract

Infusion of mesenchymal stromal cells (MSCs) is a promising and increasingly applied therapy for patients who suffer from a variety of inflammatory diseases, including graft-versus-host disease (GvHD), a common and life-threatening complication after allogeneic hematopoietic stem cell transplantation. The therapeutic effect of MSCs is mainly ascribed to their ability to suppress T cells and to support tissue repair. However, clinical response rates in patients with GvHD are limited to 50%, and the determinants for MSC responsiveness are unknown. We recently reported that high frequencies of activated group 3 innate lymphoid cells (ILC3s) before and after allogeneic hematopoietic stem cell transplantation were associated with a lower risk of GvHD. This may be related to IL-22 production by ILC3s, a cytokine important for intestinal epithelial cell homeostasis. In this study, we investigated whether ILC3s may contribute to the therapeutic effect of MSCs by studying the interaction between MSCs and ILC3s in vitro. ILC3s isolated from human tonsils were cocultured with human bone marrow-derived MSCs for 5 d in the presence of IL-2. Coculture with MSCs enhanced the proliferation and IL-22 production of ILC3s. Reciprocally, ILC3s promoted ICAM-1 and VCAM-1 expression on MSCs. For both directions, the activation was mainly mediated by cell-cell contact and by MSC-derived IL-7 and likely by aryl hydrocarbon receptor ligands. Thus, in addition to inhibiting the proliferation of alloreactive T cells, MSCs also promote the expansion and IL-22 production of ILC3s, which may contribute to healthy homeostasis and wound repair in the treatment of various inflammatory conditions in the intestine, including GvHD.

Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy

“…Accumulating evidences have demonstrated that MSCs can regulate T cell proliferation, function, balance T-helper (Th)1 and Th2 activity [69,70], upregulate the functions of regulatory T cells (Tregs) [71], suppress B cell functions [72,73], inhibit natural killer (NK) cell proliferation and function [74], and prevent dendritic cell (DC) maturation and activation [6,57,62]. MSCs can also stimulate proliferation and cytokine secretion in innate lymphoid cells (ILCs), a new family of lymphocyte-like cells, which play an important role in innate defences against pathogens [75,76]. MSCs can regulate their immunomodulatory functions according to the micro-environmental inflammatory conditions.…”

HCMV Infection in a Mesenchymal Stem Cell Niche: Differential Impact on the Development of NK Cells versus ILC3

“…Notably, we demonstrate that the large majority of CD56 + CD94cells generated on MSCs were indeed mature RORγt + , IL-22-producing ILC3, whereas this was only the case for a minor subset when generated on murine stroma cells [45]. Of note, co-culturing of MSCs with ex vivo isolated human tonsillar ILC3s was shown to enhance ILC3 proliferation and IL-22 production [51].…”

Interleukin-7 Receptor Alpha in Innate Lymphoid Cells: More Than a Marker

“…Indeed, IL-7 stimulation can induce RORγt expression and play a supportive role in IL-23 mediated IL-22 production in ILC3s (94). Furthermore, in vitro co-culture of IL-7 producing mesenchymal stromal cells (MSCs) with ILC3s led to IL-22 production and enhanced IL-2 induced proliferation of ILC3s (95). This was due to IL-7 derived from MSCs as measured by ELISA (95).…”

“…Furthermore, in vitro co-culture of IL-7 producing mesenchymal stromal cells (MSCs) with ILC3s led to IL-22 production and enhanced IL-2 induced proliferation of ILC3s (95). This was due to IL-7 derived from MSCs as measured by ELISA (95). IL-7, together with retinoic acid (RA), is also important for homing of ILCs to gut-associated tissues by upregulating ILC3-intrinsic expression of α4β7 and selectin ligands, an effect mediated by IL-7 in T cell homing as well (96,97) (Figure 4).…”