CD40 Activity on Mesenchymal Cells Negatively Regulates OX40L to Maintain Bone Marrow Immune Homeostasis Under Stress Conditions.

Barbara Bassani,Elena Jachetti,Mario P Colombo,Korinna Joehrens,Il-Kang Na,Alessandro Gulino,Paola Portararo,Niccolò Bolli,Claudia Chiodoni,Antonio Curti,Laura Botti,Ioannis Anagnostopoulos,Claudio Tripodo,Marilena Ciciarello,Sabina Sangaletti

doi:10.3389/fimmu.2021.662048

Abstract

BackgroundWithin the bone marrow (BM), mature T cells are maintained under homeostatic conditions to facilitate proper hematopoietic development. This homeostasis depends upon a peculiar elevated frequency of regulatory T cells (Tregs) and immune regulatory activities from BM-mesenchymal stem cells (BM-MSCs). In response to BM transplantation (BMT), the conditioning regimen exposes the BM to a dramatic induction of inflammatory cytokines and causes an unbalanced T-effector (Teff) and Treg ratio. This imbalance negatively impacts hematopoiesis, particularly in regard to B-cell lymphopoiesis that requires an intact cross-talk between BM-MSCs and Tregs. The mechanisms underlying the ability of BM-MSCs to restore Treg homeostasis and proper B-cell development are currently unknown.MethodsWe studied the role of host radio-resistant cell-derived CD40 in restoring Teff/Treg homeostasis and proper B-cell development in a murine model of BMT. We characterized the host cellular source of CD40 and performed radiation chimera analyses by transplanting WT or Cd40-KO with WT BM in the presence of T-reg and co-infusing WT or - Cd40-KO BM-MSCs. Residual host and donor T cell expansion and activation (cytokine production) and also the expression of Treg fitness markers and conversion to Th17 were analyzed. The presence of Cd40+ BM-MSCs was analyzed in a human setting in correlation with the frequency of B-cell precursors in patients who underwent HSCT and variably developed acute graft-versus-host (aGVDH) disease.ResultsCD40 expression is nearly undetectable in the BM, yet a Cd40-KO recipient of WT donor chimera exhibited impaired B-cell lymphopoiesis and Treg development. Lethal irradiation promotes CD40 and OX40L expression in radio-resistant BM-MSCs through the induction of pro-inflammatory cytokines. OX40L favors Teff expansion and activation at the expense of Tregs; however, the expression of CD40 dampens OX40L expression and restores Treg homeostasis, thus facilitating proper B-cell development. Indeed, in contrast to dendritic cells in secondary lymphoid organs that require CD40 triggers to express OX40L, BM-MSCs require CD40 to inhibit OX40L expression.ConclusionsCD40+ BM-MSCs are immune regulatory elements within BM. Loss of CD40 results in uncontrolled T cell activation due to a reduced number of Tregs, and B-cell development is consequently impaired. GVHD provides an example of how a loss of CD40+ BM-MSCs and a reduction in B-cell precursors may occur in a human setting.

Highlights

Bone marrow (BM) is the primary lymphoid organ and is dependent upon hematopoietic development; it is capable of activating secondary lymphoid organs
To study the regulatory role of CD40 produced by radio-resistant cells in vivo, we performed bone marrow transplant (BMT) experiments where recipient mice that were either wild type (WT) or Cd40-KO were lethally irradiated and transplanted with hematopoietic stem cells (HSC) from congenic WT donors
These data in combination with the normal B-cell lymphopoiesis of the reverse Cd40-KO>WT chimeras (Additional File 1: Supplementary Figure 2B) suggest that CD40 expression in radio-resistant cells is necessary to allow for proper BM B-cell development when CD40-competent HSCs are infused

Summary

Introduction

Bone marrow (BM) is the primary lymphoid organ and is dependent upon hematopoietic development; it is capable of activating secondary lymphoid organs. Within the BM, T lymphocytes display a peculiar CD8-to-CD4 ratio (in favor of the former) and are dispersed throughout the BM stroma and parenchyma or condensed in lymphoid tissues surrounding blood vessels Such lymphoid tissues can expand during infection and inflammation, suggesting the establishment of an effective immune response in this organ [1]. Within the bone marrow (BM), mature T cells are maintained under homeostatic conditions to facilitate proper hematopoietic development This homeostasis depends upon a peculiar elevated frequency of regulatory T cells (Tregs) and immune regulatory activities from BM-mesenchymal stem cells (BM-MSCs). In response to BM transplantation (BMT), the conditioning regimen exposes the BM to a dramatic induction of inflammatory cytokines and causes an unbalanced T-effector (Teff) and Treg ratio This imbalance negatively impacts hematopoiesis, in regard to B-cell lymphopoiesis that requires an intact cross-talk between BM-MSCs and Tregs. The mechanisms underlying the ability of BM-MSCs to restore Treg homeostasis and proper B-cell development are currently unknown

Methods

Results

Conclusion