CD4 T-cell suppression by cells from Toxoplasma gondii-infected retinas is mediated by surface protein PD-L1.
ABSTRACT In the inflamed retina, CD4(+) T cells can cause retinal damage when they are not properly regulated. Since tissue expression of major histocompatibility complex (MHC) class II and costimulatory molecules is a key mechanism for regulating effector T cells, we tested the hypothesis that upregulation of these proteins in the retina contributes to the regulation of CD4 T cells. Here we report that in retinas infected with the protozoan parasite Toxoplasma gondii, MHC class II is upregulated on infiltrating leukocytes as well as on resident retinal cells, including photoreceptors. Flow cytometric analysis indicated that B7 costimulatory family members (CD80, CD86, ICOS-L, and programmed death ligand 2 [PD-L2]) were not expressed on class II(+) cells. In contrast, PD-L1 (also named B7-H1 or CD274) was expressed on the majority of both hematopoietic and resident retinal MHC class II-expressing cells. Retinal cells from Toxoplasma-infected animals were able to suppress T-cell activation in a PD-L1-dependent manner. Finally, we demonstrate that the expression of MHC class II and PD-L1 was critically dependent on gamma interferon (IFN-gamma) expression. These data suggest that retinal MHC class II and PD-L1 expression is a novel mechanism by which the retina protects itself from CD4 T-cell-mediated immune damage in ocular toxoplasmosis and other types of retinal immune responses.
SourceAvailable from: Dirk Schlüter[Show abstract] [Hide abstract]
ABSTRACT: Ocular toxoplasmosis (OT) is considered the most frequent form of infectious posterior uveitis and is caused by the protozoan parasite Toxoplasma gondii. The resulting vision loss frequently incapacitates patients and places a considerable socio-economic burden on societies in particular in developing countries. Although, toxoplasmic retinochoroiditis is a world-wide phenomenon stark regional differences with regard to prevalence and presumably route of infection exist. This review will discuss our current clinical understanding of OT including typical and atypical manifestations, patient characteristics which influence the course of disease and treatment options. Even though, congenital and acquired OT are not regarded as separate entities, certain differences exist, which will be assessed and evaluated in detail. A strong focus is laid on the disease causing parasite T. gondii, since solving the mystery of OT aetiology and the development of improved therapies will not be possibly with clinical science alone, but rather requires a precise understanding of parasitological and immunological pathomechanisms. Additionally, the biology and genetics of T. gondii form the foundation for novel and sophisticated diagnostic methods. Scientific advances in the recent years have shed some light on the different role of T. gondii strains with regard to OT manifestation and severity of disease. Genetic and environmental factors influencing OT will be presented and commonalities between OT and toxoplasmic encephalitis will be briefly discussed. Furthermore, the laboratory tools to study OT are crucial in our understanding of OT. In vivo and in vitro experimental approaches will be summarised and evaluated extensively. Finally, a brief outlook is given in which direction OT research should be headed in the future.Progress in Retinal and Eye Research 01/2014; DOI:10.1016/j.preteyeres.2013.12.005 · 9.90 Impact Factor
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ABSTRACT: Toxoplasma and Plasmodium parasites exact a significant toll on public health. Host immunity required for efficient control of infection by these Apicomplexans involves the induction of potent T cell responses, which sometimes results in immunopathological damage. Thus, protective immune responses must be balanced by regulatory networks that limit immunopathology. We review several key cellular and molecular immunoregulatory networks operational during Toxoplasma and Plasmodium infections. Accumulating data show that despite differences in how the immune response controls these parasites, many host immunoregulatory pathways and cellular networks are common to both. Thus, understanding the cellular and molecular circuits that prevent or regulate immunopathological responses against one parasite is likely to inform our understanding of the host response to the other parasite.Trends in Parasitology 10/2013; DOI:10.1016/j.pt.2013.10.002 · 6.22 Impact Factor
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ABSTRACT: Retinal lesions or other ocular manifestations are serious consequences of infection with the protozoan parasite Toxoplasma gondii. Whilst classically considered a consequence of congenital transmission, recent screening studies estimated that 2% of T. gondii seropositive persons in Europe and North America have retinal lesions, most of them persisting unnoticed. The situation is more dramatic in South America, probably due to the predominance of virulent strains. Some of these strains seem to exhibit ocular or neuronal tropism and are responsible for severe ocular lesions. Despite the medical importance, the physiopathological mechanisms have only recently begun to be elucidated. The particular immune-privileged situation in the eye has to be considered. Studies on French patients showed low or undetectable ocular parasite loads, but a clear Th1/Th17 type immune reaction. Suitable mouse models have appeared in the last few years. Using such a model, IL-17A proved to impair parasite control and induce pathology. In contrast, in South American patients, the parasite seems to be much less efficiently controlled through a Th2 type or suppressive immune response that favors parasite replication. Finally, several host genetic markers controlling immune response factors have been associated with ocular involvement of T. gondii infection, mainly in South America.International journal for parasitology 11/2013; DOI:10.1016/j.ijpara.2013.09.007 · 3.40 Impact Factor