Saturday, September 7, 2024
9/7/2024
Inflammation negatively affects Tregs stability and suppressive function, impairs the induction of solid organ transplant tolerance and enhances acute and chronic rejection, leading to worse recipients’ long-term outcomes. Insights into key inflammatory pathways that suppress Tregs during allo-immune activation can revolutionize our therapeutic approach to promoting stable endogenous Tregs. Our work strongly suggests that an inflammatory cytokine, macrophage migration inhibitory factor (MIF), secreted by myeloid cells and alloreactive T cells during rejection and inflammation binds CD74 (MIF receptor) on the surface of activated Tregs to dampen its function and homeostasis with opposite effect on alloreactive T cells. We show that inhibiting this novel pathway either through monoclonal antibodies or genetic deletion promotes immune regulation and induce exhaustion of alloreactive T cells leading to indefinite heart allograft survival in a murine fully mismatched model. MIF is a potent pro-inflammatory cytokine produced and released by immune cells, particularly macrophages, and plays an integral role in innate immunity. However, its role in adaptive immunity is not well known and will be investigated. Our data show that graft infiltrating Tregs and Teff upregulate their expression of MIF receptor CD74. However, graft infiltrating myeloid cells and Teff but not Tregs secrete MIF. MIF then binds to CD74 on Tregs surface to suppress and on Teff to promote their function. Our single cell transcriptomic analysis, TCR sequencing, flow cytometry and functional assays showed that CD74 deficient graft infiltrating Tregs reduced Interferon regulatory factor 1 (IRF1) and shifted toward a more stable Treg phenotype that exhibits superior suppressive ability in vitro and in vivo. IRF1 is a negative regulator of Foxp3 transcriptional activity that contributes significantly to Treg instability in the setting of inflammation. Interestingly, CD74 signaling is exerted through its intracellular-domain (ICD), shown to bind to transcription factors to modulate gene expression. Recent work identified IRF1 as one of the binding TFs for CD74-ICD13. In this application we will test the hypothesis that a novel inflammatory pathway in which MIF produced by myeloid cells and Teff suppresses Treg function through IRF1 mediated CD74 signaling (SA1), while promoting the Teff function (SA2). We will also develop a clinically relevant strategy to dampen the MIF mediated inflammatory process in the allograft using anti-CD74 monoclonal antibody generated in our lab (SA3). This anti-mouse CD74 is equivalent to the FDA approved human anti CD74 (milatuzumab). Hence, this work has high translation potentials.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
