Background: Myeloid derived suppressor cells (MDSC) are myeloid cells with suppressive function, a definition that reflects both their origin and function. MDSC represent a heterogeneous population of myeloid cells at different stages of differentiation, and the suppressive function of specific MDSC subsets is not well understood. We previously demonstrated that a subset of Gr1 expressing graft infiltrating monocytic MDSC inhibit T cell proliferation in mixed lymphocyte reactions (MLR). In an effort to determine the suppressive function of MDSC subsets, we assessed their ability and the mechanisms by which they prevent T cell proliferation and mediate transplantation tolerance.

Methods: Vascularized BALB/c (H-2d) donor hearts were transplanted into fully mismatched C57BL6 (H-2b) mice. Recipients were administered anti-murine CD154 mAb at the time of transplantation for tolerance induction. Graft infiltrating MDSC subsets were sorted for gene array analysis and their ability to inhibit T cell immune responses was assessed in vitro and in vivo.

Results: In vitro MLR results indicate that the suppressive function of myeloid cells with MDSC phenotype reside in CD11b+Gr1+Ly6G-Ly6Clo expressing cells. Specific in vivo depletion of CD11b+Gr1+Ly6G-Ly6Clo MDSC prevents the induction of transplantation tolerance. Microarray analysis revealed that arachidonate lipoxygenase is specifically upregulated in Ly6Clo MDSC, and when its function was tested in vitro, we observed that Ly6Clo MDSC from arachidonate lipoxygenase deficient recipients failed to inhibit T cell proliferation in vitro.

Conclusion: These results identify CD11b+Gr1+Ly6G-Ly6Clo myeloid cells as the MDSC subset that mediates transplantation tolerance. We also identify a previously unrecognized pathway that is necessary for suppression. This suggests that the arachidonate lipoxygenase pathway may represent a new therapeutic target to facilitate transplant tolerance mediated by MDSC. Further experiments are aimed to determine whether products of the arachidonate lipoxygenase pathway facilitate suppression, whether this occurs within the MDSC or a secondary cellular target such as Treg, and whether tolerance can be induced in arachidonate lipoxygenase deficient mice.

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