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Abstract: TH-OR49

Critical Role of CD74 in Immune Regulation and Allograft Tolerance

Session Information

Category: Transplantation

  • 2001 Transplantation: Basic

Authors

  • Solhjou, Zhabiz, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Younis, Nour Khaled, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Zhang, Hengcheng, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Choi, John Yongjoon, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Saad, Anis Joseph, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Deban, Christa A., Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Halawi, Ahmad, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Bucala, Richard, Yale School of Medicine, New Haven, Connecticut, United States
  • Azzi, Jamil R., Brigham and Women's Hospital, Boston, Massachusetts, United States
Background

While known as the receptor for Microphage Inhibitory Factor (MIF) and MHC class II chaperone, the role of CD74 remains elusive in alloimmunity. We identified enriched CD74 transciptome in urinary exosome of kidney allograft rejection, thus we explored the role of CD74 in alloimmune response in a mice transplant model.

Methods

We generated universal and conditional CD74KO mice and used as recipients of murine heart allograft ina full HLA mismatch model. Graft survival assessed; with Immunophenotyping of allograft and proliferation and functional assays performed.

Results

We observed indefinite survival heart allografts in CD74KO recipients compared to WT (MST >100 vs 7 days, p=0.0008); Treg depletion resulted in allograft rejection (Fig 1,2). At day 7 post-transplantation, 5 times increase in Tregs infiltrating allograft as compared to WT noted, similar pattern with smaller magnitude observed in draining lymph node. To our suprise, higher frequency of activated effector CD4 cells (CD44+) observed in allograft of CD74KO recipients. In-vitro, activated effector CD4 cells harvested from CD74KO mice revealed decreased proliferation compared to WT. In contrast, CD74KO Tregs showed higher proliferation and suppressive function in-vitro. Naive CD4 cells show minimal CD74 expression. CD74 expression significantly increased in Tregs upon stimulation at both protein and RNA level (up to 30 times), with minimal MIF expression. Effector CD4 cells show 8 times increase in MIF expression. MIF is involved in activation of CD4 cells and we are currently studying its role in supression of Treg activity adn function.

Conclusion

Our data identifies a differential role of CD74 on regulatory and effector T cells function towards stronger regulatory and defective effector function. This contrasting cell-type specific phenotype could be at least partly due to MIF dependent CD74 inhibitory signaling of Tregs.

Funding

  • NIDDK Support