Experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 (H-2b) mice is characterized by early (day 12) acute paralysis, followed by a sustained chronic clinical course that gradually stabilizes. Extensive inflammation and demyelination coincide with clinical signs of disease. To identify the mechanisms of these processes, individual proinflammatory and anti-inflammatory cytokines and chemokines were studied. Sensitive single-cell assays were utilized to determine the cellular origin and kinetics of cytokine production in the CNS. Immunization with MOG35–55 peptide resulted in priming of both Th1 (lymphotoxin, IFN-γ, and TNF-α) and Th2 (IL-4) cells in the spleen. However, only Th1 cells were apparent in the CNS. CD4 T cells that produced IFN-γ or TNF-α were present in the CNS by day 7 after immunization with MOG35–55, peaked at day 20, and then waned. TNF-α was also produced in the CNS by Mac-1+ cells. On days 7 and 10 after immunization, the TNF-α-producing Mac1+ cells were predominantly microglia. By day 14, a switch occurred in that the Mac1+ TNF-α-producing cells had the phenotype of infiltrating macrophages. RANTES, IFN-inducible protein 10 (IP-10), and monocyte chemotactic protein 1 chemokine mRNA were detected in the CNS by day 8 after immunization. The early presence of monocyte chemotactic protein 1 (MCP-1) in the CNS provides a mechanism for the recruitment of macrophages. These data implicate TNF-α production by a continuum of T cells, microglia, and macrophages at various times during the course of disease. The importance of Th1 cytokines is highlighted, with little evidence for a role of Th2 cytokines.
To understand how adaptive immune responses are generated against bacteria that avoid being delivered to lysosomes, interactions between professional antigen-presenting cells (APCs) and the intracellular pathogen Legionella pneumophila were examined. In contrast to murine bone marrow-derived macrophages (BMMs), we show that dendritic cells (DCs) restrict the growth of intracellular Legionella. Similar to what has been reported in BMMs, phagosomes containing Legionella matured into endoplasmic reticulum (ER)-derived organelles after DC internalization. Biogenesis of an ER-derived vacuole did not effectively sequester Legionella antigens from presentation on MHC class II molecules (MHC II). It was determined that proteins synthesized after Legionella had established residence in an ER-derived vacuole were presented by infected APCs. These data indicate that the ability of DCs to restrict intracellular growth of Legionella could be an important property that facilitates priming of protective T cell-mediated immune responses to vacuolar pathogens.
SummaryIntracellular pathogens can manipulate host cellular pathways to create specialized organelles. These pathogen-modified vacuoles permit the survival and replication of bacterial and protozoan microorganisms inside of the host cell. By establishing an atypical organelle, intracellular pathogens present unique challenges to the host immune system. To understand pathogenesis, it is important to not only investigate how these organisms create unique subcellular compartments, but to also determine how mammalian immune systems have evolved to detect and respond to pathogens sequestered in specialized vacuoles. Recent studies have identified genes in the respiratory pathogen Legionella pneumophila that are essential for establishing a unique endoplasmic reticulum-derived organelle inside of mammalian macrophages, making this pathogen an attractive model system for investigations on host immune responses that are specific for bacteria that establish vacuoles disconnected from the endocytic pathway. This review will focus on the host immune response to Legionella and highlight areas of Legionella research that should help elucidate host strategies to combat infections by intracellular pathogens.
To understand how macrophages (Mφ) activated with IFN-γ modulate the adaptive immune response to intracellular pathogens, the interaction of IFN-γ-treated bone marrow-derived murine Mφ (BMφ) with Legionella pneumophila was investigated. Although Legionella was able to evade phagosome lysosome fusion initially, and was capable of de novo protein synthesis within IFN-γ-treated BMφ, intracellular growth of Legionella was restricted. It was determined that activated BMφ infected with Legionella suppressed IFN-γ production by Ag-specific CD4 and CD8 T cells. A factor sufficient for suppression of T cell responses was present in culture supernatants isolated from activated BMφ following Legionella infection. Signaling pathways requiring MyD88 and TLR2 were important for production of a factor produced by IFN-γ-treated BMφ that interfered with effector T cell functions. Cyclooxygenase-2-dependent production of PGs by IFN-γ-treated BMφ infected with Legionella was required for inhibition of effector T cell responses. From these data we conclude that activated Mφ can down-modulate Ag-specific T cell responses after they encounter bacterial pathogens through production of PGs, which may be important in preventing unnecessary immune-mediated damage to host tissues.
To better understand interactions between the intracellular pathogen Legionella pneumophila and macrophages (Ms), host and bacterial determinants important for presentation of antigens on major histocompatibility complex class II molecules (MHC-II) were investigated. It was determined that immune CD4 T-cell responses to murine bone marrow-derived Ms (BMs) infected with wild-type L. pneumophila were higher than the responses to avirulent dotA mutant bacteria. Although this enhanced response by immune T cells required modulation of vacuole transport mediated by the Dot/Icm system, it did not require intracellular replication of L. pneumophila. Intracellular cytokine staining identified a population of immune CD4 T cells that produced gamma interferon upon incubation with BMs infected with wild-type L. pneumophila that did not respond to M infection with dotA mutant bacteria. Endocytic processing was required for presentation of L. pneumophila antigens on MHC-II as determined by a defect in CD4 T-cell responses when the pH of BM endosomes was neutralized with chloroquine. Investigation of MHC-II presentation of antigens by BMs infected with L. pneumophila icmR, icmW, and icmS mutants indicated that these mutants have an intermediate presentation phenotype relative to those of wild-type and dotA mutant bacteria. In addition, it was found that antigens from dot and icm mutants are presented earlier than antigens from wild-type L. pneumophila. Although immune CD4 T-cell responses to proteins secreted by the L. pneumophila Lsp system were not detected, it was found that the Lsp system is important for priming L. pneumophila-specific T cells in vivo.These data indicate that optimal antigen processing and MHC-II presentation to immune CD4 T cells involves synthesis of L. pneumophila proteins in an endoplasmic reticulum-derived compartment followed by transport to lysosomes.Naive T cells expressing a unique T-cell receptor become antigen-specific effector cells upon encountering a professional antigen-presenting cell that has a cognate peptide major histocompatibility complex (MHC) displayed on its surface (2). Effector T cells play an important role in immunity to pathogens by producing factors that either upregulate cellular antimicrobial functions or that kill infected target cells that display a cognate peptide MHC (11,20). T cells producing the CD4 protein typically respond to peptides presented on MHC class II molecules (MHC-II), whereas a peptide-loaded MHC-I will stimulate T cells producing CD8. Most antigens loaded onto MHC-I are derived from proteins that have gained access to the cell cytosol, such as viral antigens or antigens released by bacterial pathogens that escape membrane-bound compartments and replicate in the cytosol of their host (21, 28). In contrast, peptides loaded onto MHC-II are derived from antigens that are transported to lysosomes, such as those produced by organisms that remain in vacuoles that undergo endocytic maturation after internalization by an antigen-presenting cell (8, 11).There are...
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