Friend retrovirus infection of myeloid dendritic cells impairs maturation, prolongs contact to naïve T cells, and favors expansion of regulatory T cells

Abstract

IntroductionDendritic cells (DCs) are the most potent antigen-presenting cells (APCs) of the immune system, and they are pivotal in the initiation of immune responses against viruses. 1 However, a number of viruses are able to infect DCs, and several recent studies have investigated the effect of such infections on the biology of DCs. Although only very few studies report enhanced or unchanged functions of DCs after viral infection, most viruses seem to impair functional properties of DCs (for review, see Pollara et al 2 ). These data imply that viruses infect DCs as a strategy of immune escape.In most reports that demonstrate the impairment of DCs by viruses, the morphology, phenotype, viability, and the ability to secrete cytokines of infected DCs was found to be altered, suggesting that viruses might have a significant impact on the DC-mediated initiation of an immune response in an infected host. 2 In fact, there is 1 report that directly shows that measles virus infection of DCs can result in unstable DC-T-cell contacts and, as a consequence, in impaired T-cell activation. 3 Retroviruses, such as HIV, are also known to infect DCs and interfere with their maturation. 4 Maturation of DCs can easily be measured by analyzing the expression of costimulatory molecules such as CD40, CD80, and CD86, or maturation markers like the molecule CD83. 5 However, the biological consequences of retrovirus infection of DCs for antigen presentation to T cells has not been investigated in detail so far. The most important functional properties of DCs are T-cell engagement and subsequent activation, which is the critical step in inducing adaptive immunity after infection. Since the interaction of DCs and naive T cells requires physical cell-cell contact, we used a 3D collagen matrix model 6 to investigate the contact duration and kinetics of virus-infected DCs with naive T cells. Friend virus (FV) is a retroviral complex comprised of 2 components: a replicationcompetent helper virus called Friend murine leukemia virus (F-MuLV), which is nonpathogenic in adult mice; and a replicationdefective but pathogenic component called spleen focus-forming virus (SFFV). 7 Coinfection of cells by the 2 viruses allows SFFV to spread by being packaged into F-MuLV-encoded virus particles. FV infection of susceptible adult mice induces polyclonal proliferation of erythroid precursor cells, causing severe splenomegaly. This proliferation is caused by the binding of the SFFV envelope glycoprotein to the erythropoietin receptors of nucleated erythroid cells. 8 In susceptible mice, FV subsequently transforms erythroid precursor cells, leading to fully malignant erythroleukemias. 9 However, beside erythroid precursor cells, FV can also infect a variety of other cells types, including B cells, monocytes, and granulocytes. 10 In addition, FV induces a severe generalized immunosuppression during acute infection 9,10 ; however, it is unknown whether this is the result of a functional impairment of APCs due to virus infection. Susceptibility to both FV-i...

Control of regulatory T cells is necessary for vaccine-like effects of antiviral immunotherapy by monoclonal antibodies

“…24 It is therefore possible that enhanced activation of DCs by cellular ICs may not only favor the activation of antiviral CTLs, but also may tip the balance of CD4 ϩ Th/Treg cells toward Treg differentiation. Also underlining a possible role for DCs in counteracting the appearance of induced Tregs, Balkow et al 46 reported that, in the FV model, DC precursors are infected and do not fully mature into DCs, which is crucial for expansion of FoxP3 ϩ Tregs. Should this also occur in FrCas E -infected/ nontreated mice, it is likely that limitation of viral spread on the administration of 667 would also help to preserve DC function to generate an efficient antiviral response.…”

The regulatory T-cell response during acute retroviral infection is locally defined and controls the magnitude and duration of the virus-specific cytotoxic T-cell response

“…In addition, we have previously shown that FV-infected DC can expand the population of Foxp3 ϩ cells in vitro upon presentation of antigen to naive T cells. 44 Because FV-infected DC were also found in spleens of infected mice, 44 it remains possible that virus-infected DC induce the proliferation of Treg at the site of infection. However, our current results show that CD8 ϩ T cells play a vital role in Treg expansion (Figure 3).…”

Race between Retroviral Spread and CD4+T-Cell Response Determines the Outcome of Acute Friend Virus Infection

“…Furthermore, FV also infects MHC II-expressing cells, such as B cells and macrophages (11,20,26), and bone marrow precursors of MHC II-expressing macrophages and dendritic cells (1,2). However, FV replicates mainly in nucleated erythroid precursors, which do not express MHC class II molecules and would not therefore be directly recognized by FV-specific CD4 ϩ T cells.…”