Toxoplasma gondii inhibits MHC class II expression in neural antigen-presenting cells by down-regulating the class II transactivator CIITA

Lüder, Carsten G. K.; Lang, Christine; Giraldo-Velásquez, Mario; Algner, Michaela; Gerdes, Jens; Groß, Uwe

doi:10.1016/s0165-5728(02)00320-x

Cited by 77 publications

(59 citation statements)

References 55 publications

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“…For example, parasite infection of DCs and macrophages (M⌽) appears to interfere with multiple signaling cascades involved in the maturation of DC populations that are required for the development of protective immunity (12,19,32,47,50). In addition, in the infected cell, T. gondii multiplies within a nondegradative parasitophorous vacuole (PV), and this compartment has until recently been viewed as inaccessible to the host endocytic machinery required for MHC-I presentation of endogenous antigens (52).…”

Section: Several Experimental Approaches Indicate That T-cell Activatmentioning

confidence: 99%

Presentation ofToxoplasma gondiiAntigens via the Endogenous Major Histocompatibility Complex Class I Pathway in Nonprofessional and Professional Antigen-Presenting Cells

Dzierszinski¹,

Pepper²,

Stumhofer³

et al. 2007

Infect Immun

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Challenge with the intracellular protozoan parasite Toxoplasma gondii induces a potent CD8؉ T-cell response that is required for resistance to infection, but many questions remain about the factors that regulate the presentation of major histocompatibility complex class I (MHC-I)-restricted parasite antigens and about the role of professional and nonprofessional accessory cells. In order to address these issues, transgenic parasites expressing ovalbumin (OVA), reagents that track OVA/MHC-I presentation, and OVA-specific CD8 ؉ T cells were exploited to compare the abilities of different infected cell types to stimulate CD8؉ T cells and to define the factors that contribute to antigen processing. These studies reveal that a variety of infected cell types, including hematopoietic and nonhematopoietic cells, are capable of activating an OVA-specific CD8 ؉ T-cell hybridoma, and that this phenomenon is dependent on the transporter associated with antigen processing and requires live T. gondii. Several experimental approaches indicate that T-cell activation is a consequence of direct presentation by infected host cells rather than cross-presentation. Surprisingly, nonprofessional antigen-presenting cells (APCs) were at least as efficient as dendritic cells at activating this MHC-I-restricted response. Studies to assess whether these cells are involved in initiation of the CD8 ؉ T-cell response to T. gondii in vivo show that chimeric mice expressing MHC-I only in nonhematopoietic compartments are able to activate OVA-specific CD8 ؉ T cells upon challenge. These findings associate nonprofessional APCs with the initial activation of CD8 ؉ T cells during toxoplasmosis.

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Section: Several Experimental Approaches Indicate That T-cell Activatmentioning

confidence: 99%

Presentation ofToxoplasma gondiiAntigens via the Endogenous Major Histocompatibility Complex Class I Pathway in Nonprofessional and Professional Antigen-Presenting Cells

Dzierszinski¹,

Pepper²,

Stumhofer³

et al. 2007

Infect Immun

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“…Infections with Mycobacterium bovis bacillus Calmette-Guérin (BCG), Mycobacterium tuberculosis (MTB) or Toxoplasma gondii also downregulate CIITA expression, but the precise mechanisms that are involved remain poorly defined [107][108][109]. The MTB 19-kDa lipoprotein inhibits IFN-+ -induced MHCII expression in macrophages by preventing the induction of CIITA type I and type IV mRNA.…”

Section: Repression Of Ciita Expression By Pathogensmentioning

confidence: 99%

Mini‐review: Specificity and expression of CIITA, the master regulator of MHC class II genes

et al. 2004

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The class II transactivator (CIITA) has been referred to as the "master control factor" for the expression of MHC class II (MHCII) genes. As our knowledge on the specificity and function of CIITA grows, it is becoming increasingly evident that this sobriquet is entirely justified. First, despite extensive investigations, the major target genes of CIITA remain those implicated in the presentation of antigenic peptides by MHCII molecules. Although other putative target genes have been reported, the contribution of CIITA to their expression remains indirect, controversial or comparatively minor relative to its decisive role as a regulator of MHCII and related genes. Second, the most important parameter dictating MHCII expression is by far the expression pattern of the gene encoding CIITA (MHC2TA). The vast majority of signals that activate or repress MHCII expression under physiological and pathological situations converge on one or more of the three alternative promoters that drive transcription of the MHC2TA gene. In short, with respect to its specificity and its exquisitely controlled pattern of expression, CIITA is by a long stretch the single most important transcription factor for the regulation of genes required for MHCII-restricted antigen-presentation.

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“…For example, the parasite down-modulates signaling pathways leading to programmed cell death (10,11) and can block the function of STAT-1, resulting in impaired MHC Ag presentation to T cells (12,13). In addition, T. gondii blocks both IL-12 and TNF-␣ production, and this may relate to the ability of the parasite to prevent NF-B nuclear translocation (14,15).…”

Section: Toxoplasma Gondii Interferes With Lipopolysaccharide-inducedmentioning

confidence: 99%

Toxoplasma gondii Interferes with Lipopolysaccharide-Induced Mitogen-Activated Protein Kinase Activation by Mechanisms Distinct from Endotoxin Tolerance

Kim

Butcher

Denkers

2004

The Journal of Immunology

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We show in this study that Toxoplasma gondii infection induces rapid activation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2, and stress-activated protein kinase/c-Jun N-terminal kinase MAPK, followed promptly by their deactivation in mouse macrophages. Nevertheless, when infected cells were subsequently subjected to LPS triggering, MAPK activation was severely defective, in particular in the case of p38 MAPK, which is required for LPS-triggered TNF-α and IL-12 production. Similar effects occurred during endotoxin tolerance, but the phenomena were distinct. LPS pretriggering failed to activate the major p38 MAPK kinase, MAPK kinase 3/6. Toxoplasma infection, in contrast, resulted in sustained activation of this kinase. Furthermore, endotoxin pre-exposure blocked IκBα degradation upon subsequent LPS triggering, but this was not the case for Toxoplasma preinfection. Endotoxin-mediated down-regulation of the LPS receptor, Toll-like receptor 4, has been suggested as one possible mechanism contributing to tolerance, and we found in this study that LPS down-modulated Toll-like receptor 4 expression. In contrast, Toxoplasma infection induced up-regulation of this pattern recognition receptor. Our results show that T. gondii blocks LPS-triggered cytokine production in part through MAPK inactivation, and that this occurs through pathways distinct from endotoxin-induced tolerance.

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Toxoplasma gondii inhibits MHC class II expression in neural antigen-presenting cells by down-regulating the class II transactivator CIITA

Cited by 77 publications

References 55 publications

Presentation ofToxoplasma gondiiAntigens via the Endogenous Major Histocompatibility Complex Class I Pathway in Nonprofessional and Professional Antigen-Presenting Cells

Presentation ofToxoplasma gondiiAntigens via the Endogenous Major Histocompatibility Complex Class I Pathway in Nonprofessional and Professional Antigen-Presenting Cells

Mini‐review: Specificity and expression of CIITA, the master regulator of MHC class II genes

Toxoplasma gondii Interferes with Lipopolysaccharide-Induced Mitogen-Activated Protein Kinase Activation by Mechanisms Distinct from Endotoxin Tolerance

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