Mesenchymal stem cells and T cells in the formation of Tertiary Lymphoid Structures in Lupus Nephritis

S Esmaeil Dorraji,Kristin A Fenton,Gro Østli Eilertsen,Aud-Malin K Hovd,Stine L Figenschau,Premasany Kanapathippillai,Gunnstein Bakland

doi:10.1038/s41598-018-26265-z

Abstract

Tertiary lymphoid structures (TLS) develop in the kidneys of lupus-prone mice and systemic lupus erythematosus (SLE) patients with lupus nephritis (LN). Here we investigated the presence of mesenchymal stem cells (MSCs) in the development of TLS in murine LN, as well as the role of human MSCs as lymphoid tissue organizer (LTo) cells on the activation of CD4+ T cells from three groups of donors including Healthy, SLE and LN patients. Mesenchymal stem like cells were detected within the pelvic wall and TLS in kidneys of lupus-prone mice. An increase in LTβ, CXCL13, CCL19, VCAM1 and ICAM1 gene expressions were detected during the development of murine LN. Human MSCs stimulated with the pro-inflammatory cytokines TNF-α and IL-1β significantly increased the expression of CCL19, VCAM1, ICAM1, TNF-α, and IL-1β. Stimulated MSCs induced proliferation of CD4+ T cells, but an inhibitory effect was observed when in co-culture with non-stimulated MSCs. A contact dependent increase in Th2 and Th17 subsets were observed for T cells from the Healthy group after co-culture with stimulated MSCs. Our data suggest that tissue-specific or/and migratory MSCs could have pivotal roles as LTo cells in accelerating early inflammatory processes and initiating the formation of kidney specific TLS in chronic inflammatory conditions.

Highlights

The formation of Tertiary lymphoid structures (TLS) is a dynamic process starting with sparse lymphocytic infiltrates that evolve into aggregates and eventually organize into distinct T cell areas and B-cell follicles with germinal centers[6,7]
Since Mesenchymal stem cell (MSCs) play a pivotal role in secondary lymphoid organ (SLO) function, organization, and tissue homeostasis and SLOs share similarity with TLS in function and structure[24,25], we investigated the localization of mesenchymal stem-like cells (MSLCs) in kidneys of lupus-prone mice
In young Ab− mice (6 wo), Nestin+Sca1+PDGFRα+CD45− MSLCs were mostly located in the pelvic wall, and CD45+ tissue-residential immune cells were located at the edge of the pelvic wall surrounded by MSLCs (Fig. 1a)

Summary

Introduction

The formation of TLS is a dynamic process starting with sparse lymphocytic infiltrates that evolve into aggregates and eventually organize into distinct T cell areas and B-cell follicles with germinal centers[6,7]. High expression of TNF-α in tissue can induce TLS formation in the absence of LTi cells, indicating a role for TNF-α producing myeloid cells[14]. Mesenchymal stem cell (MSCs) are adult multipotent progenitor cells, which exist in almost all tissues, and are assumed immunomodulators[17,18,19,20] This function makes them the most prominent therapeutic candidate for autoimmune and inflammatory diseases, as they can inhibit dendritic and T cell proliferation and maturation[21]. Since MSCs subsist in almost all tissues, their immunostimulatory potentials could play a fundamental role in initiating an inflammatory process in autoimmune diseases. We hypothesize that MSCs play a crucial role as LTo cells, which trigger inflammatory signaling cascade in the kidney that leads to recruitment of immune cells and subsequently TLS formation. Our results indicate that MSCs in a pro-inflammatory milieu may stimulate CD4+ T cell proliferation and differentiation into Th2 and Th17 effector cells

Methods

Results

Conclusion