Introduction: Published data in cancer models have shown that myeloid-derived suppressor cells (MDSCs) can induce antigen-specific CD8 T cell tolerance and promote tumor escape (Nagaraj et al, Nat. Med. 2007). This was thought to be mediated by an antigen-dependent disruption of the T cell receptor complex by the antigen-presenting MDSCs. We have previously shown that donor-specific transplant tolerance induced by donor splenocytes (SP) treated with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (ECDI) is dependent on the expansion of MDSCs in response to donor ECDI-SP treatment. In this study, we examined whether the MDSCs induced by donor ECDI-SP possess donor-specificity in a site-specific manner.

Methods: We used a BALB/c to C57BL/6 (B6) heart transplantation model. B6 monocytic and granulocytic MDSCs were obtained by MACS sorting. B6 2C CD8 T cells that recognize a naturally occurring ubiquitous octapeptide presented by the L^d molecule were used to demonstrate BALB/c-stimulated proliferation. OT-1 CD8 T cells were used to demonstrate OVA257-264 (SIINFEKL)-stimulated proliferation.

Results: We first examined MDSCs obtained from the spleen. Both monocytic and granulocytic MDSCs from either un-manipulated or donor (BALB/c) ECDI-SP treated B6 mice suppressed anti-CD3/CD28 stimulated CD8 T cell proliferation with equal potency. When 2C CD8 T cells were stimulated with BALB/c T-depleted splenocytes, suppression of proliferation was only observed by monocytic but not granulocytic MDSCs; and the suppression by monocytic MDSCs from ECDI-SP treated B6 mice was significantly more robust than that seen with monocytic MDSCs from un-manipulated B6 mice. We next examined the MDSCs obtained from the transplanted BALB/c cardiac allografts in donor ECDI-SP tolerized B6 recipients. Interestingly, monocytic MDSCs from tolerized BALB/c cardiac allograft suppressed 2C CD8 T cell proliferation even more robustly compared with their splenic counterparts. In contrast, when OT-1 CD8 T cells were stimulated with the SIINFEKL peptide, suppression of proliferation by MDSCs from BALB/c ECDI-SP tolerized recipients was significantly diminished compared with that observed with MDSCs from un-manipulated B6 mice.

Conclusion: MDSCs expanded in response to donor ECDI-SP suppress donor-stimulated CD8 T cell proliferation more robustly than MDSCs from un-manipulated hosts. Close contact with donor antigens at the graft site may further enhance such donor-specific suppression of the MDSCs.

CITATION INFORMATION: Zhang L., Wang J., Zhang Z., Luo X. Myeloid-Derived Suppressor Cells Suppress with Enhanced Donor Specificity in Donor ECDI-SP Treated Recipients Am J Transplant. 2017;17 (suppl 3).

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