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

Shaikh H, Pezoldt J, Mokhtari Z, Vargas JG, Le DD, Mosca JP, Viera EA, Kern MA, Graf C, Beyersdorf N, Lutz MB, Riedel A, Büttner-Herold M, Zernecke A, Einsele H, Saliba AE, Ludewig B, Huehn J, Beilhack A (2022)


Publication Type: Journal article

Publication year: 2022

Journal

Book Volume: 7

Article Number: e154250

Journal Issue: 22

DOI: 10.1172/jci.insight.154250

Abstract

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.

Authors with CRIS profile

Involved external institutions

How to cite

APA:

Shaikh, H., Pezoldt, J., Mokhtari, Z., Vargas, J.G., Le, D.D., Mosca, J.P.,... Beilhack, A. (2022). Fibroblastic reticular cells mitigate acute GvHD via MHCII-dependent maintenance of regulatory T cells. JCI Insight, 7(22). https://doi.org/10.1172/jci.insight.154250

MLA:

Shaikh, Haroon, et al. "Fibroblastic reticular cells mitigate acute GvHD via MHCII-dependent maintenance of regulatory T cells." JCI Insight 7.22 (2022).

BibTeX: Download