HIF-1α is essential for T cell suppression by murine LP-BM5 retrovirus infection-augmented Monocytic Myeloid Derived Suppressor Cells

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Abstract Compared to naïve mice, monocytic myeloid-derived suppressor cells (M-MDSCs) increase in number, and suppressive efficiency, after infection with the immunodeficiency causing mouse retrovirus, LP-BM5. In ex vivo suppression assays, M-MDSCs, enriched from spleens of LP-BM5 infected mice inhibited both T- and as a novel finding, B-cell responsiveness. For M-MDSC suppression of T-cell proliferation and IFN-gamma production, we previously reported the mechanism to be almost completely iNOS/NO dependent. In contrast, the suppression of B-cell proliferation and IL-10 secretion by predominantly T2-B cells was only ~50% iNOS/NO dependent, with V-domain Ig suppressor of T cell activation (VISTA), superoxide and peroxynitrite also playing substantial effector roles. In light of recent reports on the Hypoxia-inducible transcription factor 1, α subunit (HIF-1α) regulating the function and differentiation of MDSCs, and reports of its role as a principal regulator of NO production, we describe here the characterization of M-MDSCs from myeloid-specific HIF-1α deficient, vs. w.t., B6 mice. As early as 5 weeks post infection, enriched M-MDSC preparations from HIF-1α deficient mice were significantly impaired functionally, in some cases with a total inability, to suppress in vitro T cell responsiveness. However, these same M-MDSC preparations suppressed B-cell responsiveness at a level very similar to that of control w.t. M-MDSCs. Experiments are in progress to further understand the role HIF-1α plays in the impairment of M-MDSC ex vivo suppression of T cell proliferation and function, including a possibility that HIF-1α regulates iNOS/NO production in M-MDSCs only when in the process of suppressing T- but not B-cell targets.

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