Kidney Week

Abstract: FR-PO993

MIF-CD74 Pathway and Its Effect on Effector T Cell Exhaustion in Alloimmunity

Session Information

• Transplantation: Basic
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Transplantation

• 2101 Transplantation: Basic

Authors

• Younis, Nour Khaled, Brigham and Women's Hospital, Boston, Massachusetts, United States

Nour Khaled Younis, MD

• Al Rahy, Nadim, Brigham and Women's Hospital, Boston, Massachusetts, United States

Nadim Al Rahy, PhD

• Solhjou, Zhabiz, Brigham and Women's Hospital, Boston, Massachusetts, United States

Zhabiz Solhjou, MD

• El Kurdi, Abdullah Bilal, American University of Beirut, Beirut, Lebanon

Abdullah Bilal El Kurdi

• Zhang, Hengcheng, Brigham and Women's Hospital, Boston, Massachusetts, United States

Hengcheng Zhang, MD, PhD

• Al Chaar, Soltan, Brigham and Women's Hospital, Boston, Massachusetts, United States

Soltan Al Chaar, MD

• Djebli, Houda, Brigham and Women's Hospital, Boston, Massachusetts, United States

Houda Djebli, PhD

• Badaoui, Andrew P., Brigham and Women's Hospital, Boston, Massachusetts, United States

Andrew P. Badaoui

• Choi, John Yongjoon, Brigham and Women's Hospital, Boston, Massachusetts, United States

John Yongjoon Choi, MD

• Piecychna, Marta, Yale University, New Haven, Connecticut, United States

Marta Piecychna, MS

• Doherty, Edward H., Yale University, New Haven, Connecticut, United States

Edward H. Doherty, PhD

• Bucala, Richard, Yale University, New Haven, Connecticut, United States

Richard Bucala, MD, PhD

• Azzi, Jamil R., Brigham and Women's Hospital, Boston, Massachusetts, United States

Jamil R. Azzi, MD, PhD

Background

Our recent clinical study has shown a significant upregulation of CD74, the cognate receptor for the cytokine MIF, in the urinary exosomal mRNAs of kidney transplant recipients during rejection, highlighting this pathway's role in alloimmunity.

Methods

WT, CD74-/-, and RAG-/- B6 (H2^b) mice were transplanted with fully mismatched BALB/c (H2^d) hearts. Single-cell RNA sequencing and immunophenotyping were conducted on allografts, draining lymph nodes(dLNs), and spleens. Additionally, various studies were performed to evaluate the effect of MIF-CD74 on T cells

Results

Fully mismatched heart transplants survived indefinitely in CD74-/- hosts. Despite that, CD74-/- recipients had significantly higher % of CD8 and CD8 effector T cells in their dLNs and spleens. Also, CD74-/- T cells exhibited a more exhausted phenotype, with higher expression of LAG3 and PD1, lower CD127, and less release of Granzyme B compared to WT cells. Moreover, flow-sorted CD74-/- CD8 effector T cells exhibited lower memory response to donor antigens in vitro. CD74-/- CD4 effector T cells displayed a similar exhaustion phenotype as CD8 effector T cells. Additionally, compared to WT cells, both CD74-/- CD4 and CD8 T cells were less capable of proliferating in vitro when stimulated non-specifically, and less capable of inducing rejection in a RAG-/- heart transplant model. Our single-cell data on allograft-infiltrating T cells supported these findings. WT CD4 and CD8 effector T cells were less clonally diverse than CD74-/- cells, indicating that WT effector T cells are more antigen-specific and capable of allograft rejection. Moreover, exhaustion gene signature and pathways were significantly upregulated in CD74-/- effector T cells, while activation gene signature and pathways such as allograft rejection, IFN-g signaling, and complement were downregulated. This impairment of effector T cells in CD74-/- recipients was accompanied by superior regulatory T cell function, as we previously described.

Conclusion

CD74 deletion impairs effector T cell proliferation and activation while enhancing regulatory T cell function. The MIF-CD74 pathway exerts a differential effect on effector T cells vs regulatory T cells, potentially explaining its role in allograft rejection.