New study identifies niches that sustain Tregs

Today, Haroon Shaikh unveils in a new publication in the Journal of Clinical Investigation Insight a critical mechanism by which fibroblastic reticular cells (FRCs) mitigate acute graft-versus-host disease (aGvHD). Our study identifies how FRCs maintain regulatory T cells (Tregs) by providing T cell receptor signals via MHC class II (MHCII) surface molecules to regulate aGvHD, a severe complication following allogeneic hematopoietic cell transplantation (allo-HCT).

Our team investigated the function of MHCII on Ccl19+ FRCs in shaping the donor CD4+ T cell response during aGvHD. We found that mice lacking MHCII expression on these FRCs experienced exacerbated aGvHD, characterized by aberrant CD4+ T cell activation and significantly reduced Treg and invariant NK T (iNKT) cell expansion. This imbalance led to a loss of protection from aGvHD, even when donor Tregs were adoptively transferred.

Interestingly, while FRCs could process and present antigens and upregulate costimulatory receptors, they were not necessary for the initial activation of alloreactive CD4+ T cells. Instead, their critical role was in the maintenance and proliferation of Tregs during the effector phase of aGvHD, highlighting their immunoprotective function.

This discovery underscores the importance of FRCs in creating a supportive niche for Tregs in secondary lymphoid organs (SLOs). By maintaining Tregs through MHCII-mediated interactions, FRCs help regulate alloimmune responses, offering a potential therapeutic target for aGvHD treatment.

Why these new findings matter
Our research results provide new insights into the cellular and molecular interactions that govern immune responses in aGvHD. Understanding the role of FRCs in Treg maintenance opens up possibilities for novel therapeutic strategies, such as targeting FRCs to enhance Treg function and improve patient outcomes after allo-HCT. Our study’s findings pave the way for future exploration into the adoptive transfer of FRCs or direct targeting of these cells to mitigate aGvHD, offering hope for more effective and patient tailored treatments.

The study resulted from the interdisciplinary collaboration of research teams at Würzburg University Hospital and academic partners from Erlangen, Braunschweig in Germany, Lausanne, St. Gallen and Zurich in Switzerland. The work was supported by our German Research Council (DFG) research consortium TRR221 GvH-GvL.

Reference:

Shaikh H, Pezoldt J, Mokhtari Z, Gamboa Vargas J, Le DD, Peña Mosca J, Arellano Viera E, Kern MAG, Graf C, Beyersdorf N, Lutz MB, Riedel A, Büttner-Herold M, Zernecke A, Einsele H, Saliba AE, Ludewig B, Huehn J, Beilhack A. (2022). Fibroblastic reticular cells mitigate acute GvHD via MHCII-dependent maintenance of regulatory T cells. JCI Insight 7(22):e154250.