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

JCI Insight. 2022 Nov 22;7(22):e154250. doi: 10.1172/jci.insight.154250.


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 (MHCIIΔCcl19) 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 MHCIIΔCcl19 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.

Keywords: Antigen-presenting cells; Hematology; MHC class 2; Stem cell transplantation; Transplantation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Graft vs Host Disease* / prevention & control
  • Hematopoietic Stem Cell Transplantation* / methods
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • T-Lymphocytes, Regulatory

Grants and funding

This work was supported by grants from the German research council (DFG) to AB (SFB221, 324392634; GRK2157 P1, 270563345; FOR1586, 179902948; μBone, 401253051) and Bayerische Forschungsstifung (Fortither WP2TP3) and the Europäische Founds für Regionale Entwicklung (EFRE; Center for personalized molecular immunotherapy). The Helmholtz Institute for RNA-based Infection Research (HIRI) supported this work with a seed grant through funds from the Bavarian Ministry of Economic Affairs and Media, Energy and Technology (Grant allocation # 0703/68674/5/2017 and 0703/89374/3/2017).