Constitutive but Not Inducible Attenuation of Transforming Growth Factor β Signaling Increases Natural Killer Cell Responses without Directly Affecting Dendritic Cells Early after Persistent Viral Infection

Abstract

Rapid innate responses to viral encounters are crucial to shaping the outcome of infection, from viral clearance to persistence. Transforming growth factor ␤ (TGF-␤) is a potent immune suppressor that is upregulated early upon viral infection and maintained during chronic infections in both mice and humans. However, the role of TGF-␤ signaling in regulating individual cell types in vivo is still unclear. Using infections with two different persistent viruses, murine cytomegalovirus (MCMV) and lymphocytic choriomeningitis virus (LCMV; Cl13), in their natural rodent host, we observed that TGF-␤ signaling on dendritic cells (DCs) did not dampen DC maturation or cytokine production in the early stages of chronic infection with either virus in vivo. In contrast, TGF-␤ signaling prior to (but not during) chronic viral infection directly restricted the natural killer (NK) cell number and effector function. This restriction likely compromised both the early control of and host survival upon MCMV infection but not the long-term control of LCMV infection. These data highlight the context and timing of TGF-␤ signaling on different innate cells that contribute to the early host response, which ultimately influences the outcome of chronic viral infection in vivo. IMPORTANCEIn vivo host responses to pathogens are complex processes involving the cooperation of many different immune cells migrating to specific tissues over time, but these events cannot be replicated in vitro. Viruses causing chronic infections are able to subvert this immune response and represent a human health burden. Here we used two well-characterized viruses that are able to persist in their natural mouse host to dissect the role of the suppressive molecule TGF-␤ in dampening host responses to infection in vivo. This report presents information that allows an increased understanding of long-studied TGF-␤ signaling by examining its direct effect on different immune cells that are activated very early after in vivo viral infection and may aid with the development of new antiviral therapeutic strategies.T he coordinated effort of both the innate and the adaptive immune systems is necessary to control invasive pathogens. Rapid viral dissemination has been associated with weak host antiviral responses and viral persistence in both mice and humans (1, 2). Thus, the magnitude of initial innate responses can be critical to limit the establishment of potentially chronic infections. Human chronic infections with hepatitis C virus (HCV), hepatitis B virus (HBV), human immunodeficiency virus (HIV), and Mycobacterium tuberculosis as well as mouse infections with lymphocytic choriomeningitis virus (LCMV) and the malaria parasite are associated with the increased production and/or signaling of the immunosuppressive molecule transforming growth factor ␤ (TGF-␤) in immune cells (3-7). However, the precise role of TGF-␤-mediated suppression on innate and adaptive immune components during infection has not been fully deciphered.Among innate cells, dendritic cells (DC...

TGF-β receptor maintains CD4 T helper cell identity during chronic viral infections

“…By using inducible Tgfbr2 deletion in adult mice, we extend the aforementioned CD8 T cell findings showing that TGFβ-RII signaling (after) infection negligibly influenced endogenous polyclonal CD8 T cells responses, both early and late during chronic LCMV or MCMV infections. Similarly, we recently used both cell type-specific and the inducible ERCre Tgfbr2 deletion system to demonstrate that TGFβ-RII signaling does not significantly influence early NK or dendritic cell responses to systemic chronic LCMV or MCMV infections in vivo (50). These observations are particularly striking given the long-appreciated exogenous TGF-β-mediated suppression of cytotoxic NK, dendritic cell, and CD8 T cell responses in vitro and/or during in vivo viral infection (51-53).…”

Papel del TGF-β en la inmunidad contra los rotavirus

“…(Allen et al, 2011; Lewis et al, 2015;Marcoe et al, 2012) dLck-TGF-bRII Deleción constitutiva tardía del TGFbRII en LT Deficiencia en el desarrollo de LT intestinales específicos de LCMV y de LThf específicos de influenza en pulmón. (Marshall et al, 2015;Sheridan et al, 2014;Zhang and Bevan, 2013) ERcre-TGF-bRII Deleción inducible del TGF-bRII en todas las células La atenuación de la señalización del TGF-β no afecta las CD y NK y su capacidad par eliminar la infección aguda de MCMV y la crónica de LCMV.…”

“…( Lewis et al, 2015) dominante negativa del TGF-βRII en dichas células. En estos ratones se evidencia una disminución del número y función de las NK pero no de las CD y se atenúa la eliminación del virus Herpes y el citomegalovirus murino (MCMV), pero no la infección crónica con LCMV (Allen, et al Para tratar de evitar el problema de la alteración celular que ocurre en los ratones genéticamente modificados constitutivamente, recientemente se recurrió a ratones ERcre-TGF-βRII que al ser tratados con tamoxifeno tienen una deleción inducible del TGF-βRII en todas las células del organismo.…”

“…En estos ratones se evidencia una disminución del número y función de las NK pero no de las CD y se atenúa la eliminación del virus Herpes y el citomegalovirus murino (MCMV), pero no la infección crónica con LCMV (Allen, et al Para tratar de evitar el problema de la alteración celular que ocurre en los ratones genéticamente modificados constitutivamente, recientemente se recurrió a ratones ERcre-TGF-βRII que al ser tratados con tamoxifeno tienen una deleción inducible del TGF-βRII en todas las células del organismo. Con estos ratones se mostró que la atenuación de la señalización del TGF-β no afecta la función de las CD ni de las NK y estas células parecen mediar la eficiente eliminación aguda de MCMV y la crónica de LCMV (Lewis , et al, 2015). En forma coherente, se ha visto que estos ratones, con deficiencia en la señalización del TGF-β inducida en la vida adulta, no desarrollan autoinmunidad (Sledzinska, et al, 2013).…”

SATB1 Expression Governs Epigenetic Repression of PD-1 in Tumor-Reactive T Cells

“…For instance, epigenetic changes induced by tumor-driven metabolic restrictions suppress T-cell activity (Zhao et al, 2016). In addition, TGF-β, an immunosuppressive mediator expressed at high levels in most established malignancies, does not play a crucial role in the pathogenesis of many viral infections (Flavell et al, 2010; Furuya et al, 2015; Garidou et al, 2012; Lewis et al, 2015; Wrzesinski et al, 2007). Thus, tumors induce dendritic cells (DCs), as well as conventional and regulatory T (Treg) cells to secrete TGF-β, which impairs effector T-cell activity through multiple mechanisms that include Foxp1-mediated transcriptional repression (Stephen et al, 2014) and suppression of effector cytokines (Ahmadzadeh and Rosenberg, 2005).…”