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Group 2 Innate lymphoid cells promote allograft survival by constraining and inducing anergy in alloreactive CD4+ T cells

ABSTRACT: Despite significant improvements in solid organ transplant outcomes over the past several decades, our limited understanding of the immune interface between donor organs and recipient immune systems has hindered the development of strategies to expand immunoregulatory cell populations and induce immune tolerance in transplant recipients. Given that group 2 innate lymphoid cells (ILC2s) are resident in transplanted solid organs, play a role in wound healing, and coordinate immunoregulatory cell populations, we sought to investigate their function in the alloimmune response. Using a murine heterotopic cardiac transplant model, we demonstrate that recipient ILC2s replace donor ILC2s and upregulate MHC class II (MHCII) without expressing costimulatory molecules. These recipient-derived ILC2s process and present alloantigens, inducing CD4+ T cell anergy through the Caspase-3-dependent pathway. In the absence of recipient-derived ILC2s, we observed a marked increase in infiltrating donor-reactive CD4+ T cells and significantly reduced allograft survival. Furthermore, in vivo expansion of ILC2s via IL-33 administration prolonged murine heart allograft survival. Collectively, these findings reveal a critical and previously unrecognized immunoregulatory role of host-derived ILC2s in solid organ transplantation, where they promote alloimmune tolerance by inducing anergy in alloreactive CD4+ T cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE290285 | GEO | 2025/10/01

REPOSITORIES: GEO

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Project description:Acute and chronic rejection continue to represent serious challenges in transplant medicine. Current medical regimens focus on suppressing T-cell responses, lack effectiveness for some patients and impose significant risks of infection and malignancy. Recent studies have suggested that inhibition of co-stimulation pathways between antigen presenting cells (dendritic cells, macrophages, B-cells) and T-cells may serve as an effective strategy to prevent rejection by promoting allograft tolerance as opposed to simply suppressing immune responses. This concept has garnered excitement across the transplant community and demonstrated promising results in human renal transplant studies. A commonly used approach is inhibition of B7-CD28 and CD40-CD40L costimulatory pathways. Blocking these pathways leads to prolonged allograft survival in fully HLA-mismatched mouse heart transplantation models and non-human primates. There are important gaps in knowledge pertaining to mechanisms by which co-stimulation blockade modulates the recipient immune responses and confers donor organ tolerance. The precise immune cell populations and mechanisms responsible for induction and maintenance of donor organ tolerance remain incompletely understood. We have leveraged single cell RNA sequencing to dissect how traditional immunosuppression (cyclosporine) and co-stimulation blockade (CTLA-4 Ig, anti-CD40L neutralizing antibodies) differentially impact the immune landscape of the transplanted heart using a fully HLA-mismatched mouse model (Balb/c donor heart à B6 recipient). Analysis of these datasets demonstrated striking differences between these treatment regimens. Mice that received co-stimulation blockade displayed a marked increase in the abundance of classical dendritic cells (cDC1s and cDC2s). Compared to the cyclosporine treated group, these cells expressed negative regulators of T-cell stimulation including PDL1. Using recipient mice that lack either cDC1s or cDC2s, we found that cDC1s are absolutely required for co-stimulation blockade to confer long-term allograft survival and prevent recipient immune responses against the transplanted donor heart.

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Group 2 Innate lymphoid cells promote allograft survival by constraining and inducing anergy in alloreactive CD4+ T cells

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