Effect of interferon‐γ on antigen processing in human monocytes

Nadler, Steven G.; Rankin, Bruce; Moran‐Davis, Patty; Cleaveland, Jeffrey S.; Kiener, Peter A.

doi:10.1002/eji.1830241232

Cited by 19 publications

(17 citation statements)

References 24 publications

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“…Building on the observation that M. tuberculosis cells as well as alkalinization of the endosomal-lysosomal compartment prevent surface expression of MHC class II ␣ and ␤ chains, leading to their intracellular sequestration (20), a BCG ureasenegative mutant generated by allelic exchange (42) was used in this study along with the human monocytic cell line THP-1 to investigate the effect of ureolytic activity on MHC class II expression. THP-1 cells display many characteristics of the mature monocyte (45) and, when differentiated with PMA, represent a versatile human macrophage model for studying several cell activities, including class II expression and antigen presentation (4,19,20,31).…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium bovisBCG Urease Attenuates Major Histocompatibility Complex Class II Trafficking to the Macrophage Cell Surface

et al. 2004

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We have previously shown that Mycobacterium tuberculosis attenuates cell surface expression of major histocompatibility complex class II molecules in response to gamma interferon (IFN-␥) by a mechanism dependent on intracellular sequestration of ␣,␤ dimers. In this study we examined whether intracellular alkalinization due to mycobacterial urease could account for the defect in intracellular trafficking of class II molecules. Phagocytosis of wild-type Mycobacterium bovis BCG was associated with secretion of ammonia intracellularly, which increased substantially upon addition of exogenous urea to the culture medium. Increased intracellular ammonia, due to urea degradation by the bacterium, correlated with inhibition of class II surface expression. Conversely, no ammonia was detected in cells infected with a urease-negative mutant strain of M. bovis BCG, which also displayed a reduced effect on surface expression of class II molecules. A direct cause-effect relationship between urease and class II molecule trafficking was established with experiments where cells ingesting beads coated with purified urease showed an increased ammonia level and decreased surface expression of class II in response to IFN-␥. In contrast to BCG, infection of macrophages with Mycobacterium smegmatis, which expresses relatively greater urease activity in cell-free culture, had a marginal effect on both the intracellular level of ammonia and class II expression. The limited effect of M. smegmatis was consistent with a failure to resist intracellular killing, suggesting that urease alone is not sufficient to resist macrophage microbicidal mechanisms and that this is required for a more distal effect on cell regulation. Our results demonstrate that alkalinization of critical intracellular organelles by pathogenic mycobacteria expressing urease contributes significantly to the intracellular retention of class II dimers.

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Section: Discussionmentioning

confidence: 99%

Mycobacterium bovisBCG Urease Attenuates Major Histocompatibility Complex Class II Trafficking to the Macrophage Cell Surface

et al. 2004

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“…Additionally, nonpresenting functions of HLA molecules have also been described. HLA molecules can, for instance, act as coreceptors of an as yet unidentified receptor and/or ligand and also transduce cell surface activation signal to the nucleus [43][44][45]. Similar roles in sperm cells are then conceivable.…”

Section: Possible Biological Role Of Hla Expression On Spermatozoamentioning

confidence: 97%

Diploid Expression of Human Leukocyte Antigen Class I and Class II Molecules on Spermatozoa and their Cyclic Inverse Correlation with Inhibin Concentration1

Martín-Villa

Luque

Martı́nez-Quiles

et al. 1996

Biology of Reproduction

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A diploid expression of class I and class II human leukocyte antigens (HLA) has been found in purified spermatozoa by using double fluorescence labeling cytofluorometry and relevant monoclonal antibodies; this expression has been confirmed for the first time by the analysis of specific HLA mRNA and metabolic 35S labeling followed by immunoprecipitation, which demonstrates an active ongoing translation of HLA proteins in germinal cells. Long-living mRNA coming from diploid germinal cells may be translated to HLA molecules in spermatozoa. This translation is controlled (or at least inversely correlated) by a testicular hormone (inhibin) in a cyclic fashion. Remarkably, serum levels of inhibin, synthesized by Leydig and Sertoli cells, follow a 12- to 13-day cycle, with a peak level at Day 6; this is probably controlled by FSH (not cyclic in males) and other testicular and/or unknown hormones. Peak levels of inhibin concur with the lower density and percentage of spermatozoa expressing both HLA class I and II molecules (close to 3% by cytofluorometry); lowest levels of inhibin coincide with the highest numbers (35-40%) of spermatozoa positive for both HLA molecules and a higher surface density. These observations could put to an end a disconcerting and long-lasting controversy on the expression/non-expression of HLA antigens on spermatozoa. The possibility that HLA-bearing spermatozoa are more capacitated for fertilization than those that do not bear HLA, and the implications of our results on male fertility control are also discussed.

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“…Decreasing IFN-␥ levels seems to have its beneficial effects through a reduction in the level of MHC II on the surface of APCs (62), reduced T cell proliferation (64), and reduced production of NO (65). Alterations in IFN-␥ levels have also been associated with differential processing and presentation of antigenic peptides on class II (66,67) through the selective regulation of the cathepsins (68,69). Consistent with the importance of IFN-␥ in the disease manifestations of SLE is the finding that IL-12 is also elevated in autoimmune mouse models (70,71).…”

Section: Discussionmentioning

confidence: 99%

T Cell Studies in a Peptide-Induced Model of Systemic Lupus Erythematosus

Khalil

Inaba

Steinman

et al. 2001

The Journal of Immunology

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We have previously reported that immunization with a peptide mimetope of dsDNA on a branched polylysine backbone (DWEYSVWLSN-MAP) induces a systemic lupus erythematosus-like syndrome in the nonautoimmune BALB/c mouse strain. To understand the mechanism underlying this breakdown in self tolerance, we examined the role of T cells in the response. Our results show that the anti-foreign and anti-self response induced by immunization is T cell dependent and is mediated by I-Ed-restricted CD4+ T cells of the Th1 subset. In addition, generation of the critical T cell epitope requires processing by APCs and depends on the presence of both DWEYSVWLSN and the MAP backbone. The breakdown in self tolerance does not occur through cross-reactivity between the T cell epitope of DWEYSVWLSN-MAP and epitopes derived from nuclear Ags. In this induced-model of SLE, therefore, autoreactivity results from the activation of T cells specific for foreign Ag and of cross-reactive anti-foreign, anti-self B cells. Despite the fact that tissue injury is mediated by Ab, the critical initiating T cell response is Th1.

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Effect of interferon‐γ on antigen processing in human monocytes

Cited by 19 publications

References 24 publications

Mycobacterium bovisBCG Urease Attenuates Major Histocompatibility Complex Class II Trafficking to the Macrophage Cell Surface

Mycobacterium bovisBCG Urease Attenuates Major Histocompatibility Complex Class II Trafficking to the Macrophage Cell Surface

Diploid Expression of Human Leukocyte Antigen Class I and Class II Molecules on Spermatozoa and their Cyclic Inverse Correlation with Inhibin Concentration1

T Cell Studies in a Peptide-Induced Model of Systemic Lupus Erythematosus

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