Enforced Expression of Mitochondrial Calcium Uniporter in Donor T Cells Abolishes Gvhd Progression

• Published in: Blood 2024-11, Vol.144 (Supplement 1), p.3403-3403
• Main Authors: WANG, Ying, Li, Alicia Huaze, sanders-Braggs, Ruqayyah, Zhou, Yan, Chen, Mimi, Bui, Tien, Zhu, Hongfa, Hossain, Nasheed, Soboloff, Jonathan, Elrod, John, Hexner, Elizabeth O., Zhang, Yi
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-212312

During the early/intermediate phases of the immune response, calcium (Ca2+) signals are crucial for T cell activation, proliferation and effector differentiation. Yet, inhibiting Ca2+ signaling-activated master transcription factor NFAT has achieved limited success in the long-term restriction of graft-versus-host disease (GVHD), while high remission and infection rates remain major issues. This underscores the need to better understand how different calcium channels coordinate to regulate T cell alloimmunity. Mitochondria is one of the two intracellular calcium stores that buffers and modulates cytosolic Ca2+ response. Mitochondria calcium uniporter (MCU) complex is the sole channel through which Ca2+ enters the mitochondria. The role of MCU in T cell-mediated GVHD remains undetermined. In this study, we report that enforced Mcu expression in donor T cells abolished their capacity to induce lethal GVHD. Using retroviral gene delivery system to induce or constitutively overexpress Mcu in T cells, we discovered that Mcu ectopic expression impaired donor T cell survival. RNA-seq analysis identified the activation of gene programs mediating death of activated T cells. This was induced by persistent alloantigen exposure (restimulation-induced cell death, RICD), leading to massive cell death in the liver, a GVHD target organ. Pharmacological enhancement of MCU function with a natural compound phenocopied this finding while preserving anti-leukemia potency. These data indicate that boosting MCU function in donor T cells could be a novel and effective strategy to mitigate GVHD after allogeneic hematopoietic stem cell transplantation. Interestingly, we discovered T cells naturally downregulated MCU function during differentiation, indicating intrinsic repressive mechanisms that protect T cells from RICD. This led us to interrogate whether MCU is required for T cell alloimmunity. We generated T cell-specific Mcu conditional knockout C57/BL6 mice (Mcu-cKO). Balb/c recipients infused with Mcu-KO B6 mouse T cells developed severe liver GVHD, manifested by the dramatically reduced liver size, bile duct lesion, portal and lobular inflammation associated with massive lymphocyte infiltration. However, these Mcu-KO T cell recipients survived longer with 69% compared to 100% mortality in WT T cell recipients. Mechanistic studies showed Mcu-KO recipients had significantly fewer donor T cells in the spleen and liver, attributed to reduced proliferation capacity; and decreased