Preemptive donor apoptotic cell infusions induce IFN-γ-producing myeloid-derived suppressor cells for cardiac allograft protection

• Published in: The Journal of immunology (1950) Vol. 192; no. 12; pp. 6092 - 6101
• Main Authors: Bryant, Jane, Lerret, Nadine M, Wang, Jiao-Jing, Kang, Hee-Kap, Tasch, James, Zhang, Zheng, Luo, Xunrong
• Format: Journal Article
• Language: English
• Published: United States 15.06.2014
• Subjects: Allografts; Animals; Apoptosis; Graft Survival - immunology; Heart Transplantation; Interferon-gamma - immunology; Male; Mice; Mice, Inbred BALB C; Myeloid Cells - immunology; Spleen - immunology; Spleen - transplantation
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1302771

We have previously shown that preemptive infusion of apoptotic donor splenocytes treated with the chemical cross-linker ethylcarbodiimide (ECDI-SPs) induces long-term allograft survival in full MHC-mismatched models of allogeneic islet and cardiac transplantation. The role of myeloid-derived suppressor cells (MDSCs) in the graft protection provided by ECDI-SPs is unclear. In this study, we demonstrate that infusions of ECDI-SPs increase two populations of CD11b(+) cells in the spleen that phenotypically resemble monocytic-like (CD11b(+)Ly6C(high)) and granulocytic-like (CD11b(+)Gr1(high)) MDSCs. Both populations suppress T cell proliferation in vitro and traffic to the cardiac allografts in vivo to mediate their protection via inhibition of local CD8 T cell accumulation and potentially also via induction and homing of regulatory T cells. Importantly, repeated treatments with ECDI-SPs induce the CD11b(+)Gr1(high) cells to produce a high level of IFN-γ and to exhibit an enhanced responsiveness to IFN-γ by expressing higher levels of downstream effector molecules ido and nos2. Consequently, neutralization of IFN-γ completely abolishes the suppressive capacity of this population. We conclude that donor ECDI-SPs induce the expansion of two populations of MDSCs important for allograft protection mediated in part by intrinsic IFN-γ-dependent mechanisms. This form of preemptive donor apoptotic cell infusions has significant potential for the therapeutic manipulation of MDSCs for transplant tolerance induction.