Impairment of Thymus-Dependent Responses by Murine Dendritic Cells Infected with Foot-and-Mouth Disease Virus

Abstract

Foot-and-mouth disease virus (FMDV) is a cytopathic virus that experimentally infects mice, inducing a thymus-independent neutralizing Ab response that rapidly clears the virus. In contrast, vaccination with UV-inactivated virus induces a typical thymus-dependent (TD) response. In this study we show that dendritic cells (DCs) are susceptible to infection with FMDV in vitro, although viral replication is abortive. Infected DCs down-regulate the expression of MHC class II and CD40 molecules and up-regulate the expression of CD11b. In addition, infected DCs exhibit morphological and functional changes toward a macrophage-like phenotype. FMDV-infected DCs fail to stimulate T cell proliferation in vitro and to boost an Ab response in vivo. Moreover, infection of DCs in vitro induces the secretion of IFN-γ and the suppressive cytokine IL-10 in cocultures of DCs and splenocytes. High quantities of these cytokines are also detected in the spleens of FMDV-infected mice, but not in the spleens of vaccinated mice. The peak secretion of IFN-γ and IL-10 is concurrent with the suppression of Con A-mediated proliferation of T cells obtained from the spleens of infected mice. Furthermore, the secretion of these cytokines correlates with the suppression of the response to OVA, a typical TD Ag. Thus, infection of DCs with FMDV induces suppression of TD responses without affecting the induction of a protective thymus-independent response. Later, T cell responses are restored, setting the stage for the development of a long-lasting protective immunity.

The Early Protective Thymus-Independent Antibody Response to Foot-and-Mouth Disease Virus Is Mediated by Splenic CD9+B Lymphocytes

“…A similar type of response has been described for other viruses such as vesicular stomatitis virus (VSV) (5,58). We have recently shown that during the early phase of the response against infectious FMDV, there is a transient but generalized suppression of TD responses (51). This effect is mediated, at least in part, by the downregulation of major histocompatibility complex class II and CD40 molecules on dendritic cells (DCs) and by the production of interleukin-10 (IL-10) by splenocytes (51).…”

“…Bone marrow-derived DCs were obtained as previously described (51). Infection of DCs was performed with FMDV serotype O1 Campos, provided by the Servicio Nacional de Sanidad y Calidad Agroalimentaria, Argentina, at a multiplicity of infection (MOI) of 10 for 4 h at 37°C.…”

“…Noninfectious UV-FMDV was prepared by the irradiation of the viral suspension with UV light as described previously (51). DCs were incubated with UV-FMDV at an MOI equivalent (measured before UV inactivation) of 10 for 4 h at 37°C.…”

“…We have recently shown that during the early phase of the response against infectious FMDV, there is a transient but generalized suppression of TD responses (51). This effect is mediated, at least in part, by the downregulation of major histocompatibility complex class II and CD40 molecules on dendritic cells (DCs) and by the production of interleukin-10 (IL-10) by splenocytes (51). In contrast, the antibody response against UV-inactivated FMDV (UV-FMDV) proceeds as a typical TD response.…”

Foot-and-Mouth Disease Virus Exhibits an Altered Tropism in the Presence of Specific Immunoglobulins, Enabling Productive Infection and Killing of Dendritic Cells

“…UV inactivation was used to cross-link the FMDV RNA genome and prevent replication while retaining the capsid structure. The protocol used was based on that of Ostrowski et al (44) with some minor modifications. FMDV was transferred to tissue culture plates on ice to a depth of no greater than 2 mm at a distance of 10 cm from the UV source (UVP, Upland, CA).…”