Type I and Type II Interferon Coordinately Regulate Suppressive Dendritic Cell Fate and Function during Viral Persistence

Abstract

Persistent viral infections are simultaneously associated with chronic inflammation and highly potent immunosuppressive programs mediated by IL-10 and PDL1 that attenuate antiviral T cell responses. Inhibiting these suppressive signals enhances T cell function to control persistent infection; yet, the underlying signals and mechanisms that program immunosuppressive cell fates and functions are not well understood. Herein, we use lymphocytic choriomeningitis virus infection (LCMV) to demonstrate that the induction and functional programming of immunosuppressive dendritic cells (DCs) during viral persistence are separable mechanisms programmed by factors primarily considered pro-inflammatory. IFNγ first induces the de novo development of naive monocytes into DCs with immunosuppressive potential. Type I interferon (IFN-I) then directly targets these newly generated DCs to program their potent T cell immunosuppressive functions while simultaneously inhibiting conventional DCs with T cell stimulating capacity. These mechanisms of monocyte conversion are constant throughout persistent infection, establishing a system to continuously interpret and shape the immunologic environment. MyD88 signaling was required for the differentiation of suppressive DCs, whereas inhibition of stimulatory DCs was dependent on MAVS signaling, demonstrating a bifurcation in the pathogen recognition pathways that promote distinct elements of IFN-I mediated immunosuppression. Further, a similar suppressive DC origin and differentiation was also observed in Mycobacterium tuberculosis infection, HIV infection and cancer. Ultimately, targeting the underlying mechanisms that induce immunosuppression could simultaneously prevent multiple suppressive signals to further restore T cell function and control persistent infections.

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

“…However, T1-IFNs can also induce anti-inflammatory responses to control immune-mediated tissue damage during chronic infections. These contradictory effects of T1-IFNs in different situations can likely be ascribed to the heterogeneity of the T1-IFNs family, downstream activation of different STAT homo/heterodimers after binding to IFNAR (38, 42) and to differential priming of cells prior to induction of T1-IFN signaling (43). …”

“…It has been observed in different mouse models, including Mtb-infected mice, that T1-IFNs can only induce an IL-10 high regulatory phenotype in monocyte-derived DCs (iregDC) if these cells have been primed previously by IFN-γ (43). IFN-γ-primed DCs that did not receive T1-IFN signaling differentiated into iDC that stimulated robust T-cell responses.…”

“…(1) T1-IFN induces migration of CCR2 + monocytes (iMo) from the bone marrow to the lungs of Mtb-infected mice under influence of CCL2 (72). Locally, these cells develop into CD11b + Ly6C high inflammatory macrophages (iM) and CD11b + Ly6C int inflammatory dendritic cells (iDC) (43). (2) As shown in Figure 1, naïve iM and iDC can initiate either IL-1β-mediated inflammation or T1-IFN-mediated inflammation.…”

“…(4) Similar to the situation in gut infection, we propose that in tuberculosis (TB) IL-12 production in the lungs stimulates IFN-γ production by bone-marrow-resident NK cells, which locally primes monocytes (154). IFN-γ priming of monocyte-derived iDC is necessary for T1-IFNs to induce a regulatory (iregDC) phenotype in iDC in the lungs (43). (5) Additionally, IFN-γ stimulates monopoiesis over granulopoiesis by granulocyte/macrophage progenitor cells (128).…”

ISG15 in the tumorigenesis and treatment of cancer: An emerging role in malignancies of the digestive system

“…This mechanism was also shown to be involved in persistent lymphocytic choriomeningitis virus, HIV, and M. tuberculosis infections [16]. Although both viruses and cancer can induce the secretion of type I IFNs, whether patterns of enhanced ISG15 expression and ISGylation in cancer cells represent cellular responses to cancer or are merely by-products of cellular processes that have been altered by tumorigenesis is unclear.…”