MiR-155 and LP-BM5 retrovirus-augmented Monocytic myeloid derived suppressor cells, are players in a profound murine immunodeficiency-causing syndrome

Abstract

Abstract We have shown augmentation of monocytic MDSCs (M-MDSCs) during a profound immunodeficiency causing LP-BM5 retrovirus infection of B6 mice. Enriched splenic M-MDSCs preparations in suppression assays, inhibited T-, and the much less reported B-, cell responsiveness. This inhibition of T-cell proliferation and IFN-gamma production was almost completely iNOS/NO dependent, whereas suppression of B-cell responses was only ~50% iNOS/NO dependent. To explore additional mechanism(s) in this inhibition of B-cell responsiveness, we reported that VISTA, a negative checkpoint regulator, is involved in LP-BM5 M-MDSC suppression of ex vivo B-cell responses. In light of the reported involvement of miR-155 in B-cell and myeloid cell function, we are now also evaluating M-MDSCs from 5 week LP-BM5 infected miR-155 k.o.s. Our results show miR-155 k.o. M-MDSCs are substantially less (30–50%) suppressive compared to M-MDSCs from infected Wt. mice, and at 10 w.p.i. the k.o.s exhibit a different kind of immunodeficiency: 1) spleen cells are significantly more responsive to B-cell polyclonal activators, 2) significantly less splenomegaly and 3) have fewer resident splenic M-MDSCs. In an initial experiment, involving adoptive transfer of M-MDSCs from donor LP-BM5 infected Wt. B6 to infected miR-155 k.o.s, we were able to significantly augment miR-155 k.o.: 1) splenomegaly, 2) splenic B-and T-cell immunodeficiency, and 3) the number of residing splenic M-MDSCs, to levels almost comparable to those of Wt. infected mice. These results highlight involvement of multiple and unique suppressive pathways in the under-studied area of MDSC suppression of B-cell responses, and were compatible with a role for M-MDSC in LP-BM5-induced immunodeficiency.