Journal Article

Fibroblastic reticular cells mitigate acute GvHD via MHCII-dependent maintenance of regulatory T cells

Shaikh, Haroon, Riedel, Angela, Mokhtari, Zeinab, Lutz, Manfred B., Beyersdorf, Niklas, Graf, Caroline, Büttner-Herold, Maike, Le, Duc-Dung, Huehn, Jochen, Pezoldt, Joern, Gamboa Vargas, Juan, Arellano Viera, Estibaliz, Kern, Michael A.G., Saliba, Antoine-Emmanuel, Zernecke, Alma, Peña Mosca, Josefina, Ludewig, Burkhard, Einsele, Hermann, Beilhack, Andreas

2022

Overview

Acute graft versus host disease (aGvHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) inflicted by alloreactive T cells primed in secondary lymphoid organs (SLOs) and subsequent damage to aGvHD target tissues. In recent years, Treg transfer and/or expansion has emerged as a promising therapy to modulate aGvHD. However, cellular niches essential for fostering Tregs to prevent aGvHD have not been explored. Here, we tested whether and to what extent MHC class II (MHCII) expressed on Ccl19 + fibroblastic reticular cells (FRCs) shape the donor CD4 + T cell response during aGvHD. Animals lacking MHCII expression on Ccl19 -Cre–expressing FRCs (MHCII ΔCcl19 ) showed aberrant CD4 + T cell activation in the effector phase, resulting in exacerbated aGvHD that was associated with significantly reduced expansion of Foxp3 + Tregs and invariant NK T (iNKT) cells. Skewed Treg maintenance in MHCII ΔCcl19 mice resulted in loss of protection from aGvHD provided by adoptively transferred donor Tregs. In contrast, although FRCs upregulated costimulatory surface receptors, and although they degraded and processed exogenous antigens after myeloablative irradiation, FRCs were dispensable to activate alloreactive CD4 + T cells in 2 mouse models of aGvHD. In summary, these data reveal an immunoprotective, MHCII-mediated function of FRC niches in secondary lymphoid organs (SLOs) after allo-HCT and highlight a framework of cellular and molecular interactions that regulate CD4 + T cell alloimmunity.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: Allografts / Animal models / Animals / Antigen presentation / Approximation / CD4 antigen / Cell activation / Cell culture / Cells / Foxp3 protein / Gene expression / Graft versus host disease / Graft vs Host Disease - prevention & control / Graft-versus-host reaction / Hematology / Hematopoietic Stem Cell Transplantation - methods / Hematopoietic stem cells / Homeostasis / Immunoregulation / Lymphatic system / Lymphocytes / Lymphocytes T / Major histocompatibility complex / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / Stem cell transplantation / T-Lymphocytes, Regulatory / Transplantation