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Multiple mechanisms allow Mycobacterium tuberculosis to continuously inhibit MHC class II-mediated antigen presentation by macrophages.

ABSTRACT: Previous experimental studies suggest that Mycobacterium tuberculosis inhibits a number of macrophage intracellular processes associated with antigen presentation, including antigen processing, MHC class II expression, trafficking of MHC class II molecules, and peptide-MHC class II binding. In this study, we investigate why multiple mechanisms have been observed. Specifically, we consider what purpose multiple mechanisms may serve, whether experimental protocols favor the detection of some mechanisms over others, and whether alternative mechanisms exist. By using a mathematical model of antigen presentation in macrophages that tracks levels of various molecules, including peptide-MHC class II complexes on the cell surface, we show that mechanisms targeting MHC class II expression are effective at inhibiting antigen presentation, but only after a delay of at least 10 h. By comparison, the effectiveness of mechanisms targeting other cellular processes is immediate, but may be attenuated under certain conditions. Therefore, targeting multiple cellular processes may represent an optimal strategy for M. tuberculosis (and other pathogens with relatively long doubling times) to maintain continuous inhibition of antigen presentation. In addition, based on a sensitivity analysis of the model, we identify other cellular processes that may be targeted by such pathogens to accomplish the same effect, representing potentially novel mechanisms.

SUBMITTER: Chang ST

PROVIDER: S-EPMC555518 | biostudies-literature | 2005 Mar

REPOSITORIES: biostudies-literature

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Multiple mechanisms allow Mycobacterium tuberculosis to continuously inhibit MHC class II-mediated antigen presentation by macrophages.

Chang Stewart T ST Linderman Jennifer J JJ Kirschner Denise E DE

Proceedings of the National Academy of Sciences of the United States of America 20050314 12

Previous experimental studies suggest that Mycobacterium tuberculosis inhibits a number of macrophage intracellular processes associated with antigen presentation, including antigen processing, MHC class II expression, trafficking of MHC class II molecules, and peptide-MHC class II binding. In this study, we investigate why multiple mechanisms have been observed. Specifically, we consider what purpose multiple mechanisms may serve, whether experimental protocols favor the detection of some mecha ...[more]

PMID: 15767567

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Project description:Macrophages are innate immune cells that internalize and present exogenous antigens to T cells via MHC class II proteins. They operate at sites of infection in a highly inflammatory environment, generated in part by reactive oxygen species, in particular the strong oxidant hypochlorous acid (HOCl) produced in the neutrophil respiratory burst. HOCl effectively kills a broad range of pathogens but can also contribute to host tissue damage at sites of inflammation. To prevent tissue injury, HOCl is scavenged by human serum albumin (HSA) and other plasma proteins in interstitial fluids, leading to the formation of variously modified advanced oxidation products (AOPPs) with pro-inflammatory properties. Previously, we showed that HOCl-mediated N-chlorination converts HSA and other plasma proteins into efficient activators of the phagocyte respiratory burst, but the role of these AOPPs in antigen presentation by macrophages remained unclear. Here, we show that physiologically relevant amounts of N-chlorinated HSA can strongly impair the capacity of THP-1-derived macrophages to present antigens to antigen-specific T cells via MHC class II proteins at multiple stages. Initially, N-chlorinated HSA inhibits antigen internalization by converting antigens into scavenger receptor (SR) ligands and competing with the modified antigens for binding to SR CD36. Later steps of antigen presentation, such as intracellular antigen processing and MHC class II expression are negatively affected, as well. We propose that impaired processing of pathogens or exogenous antigens by immune cells at an initial stage of infection prevents antigen presentation in an environment potentially hostile to cells of the adaptive immune response, possibly shifting it towards locations removed from the actual insult, like the lymph nodes. On the flip side, excessive retardation or complete inhibition of antigen presentation by N-chlorinated plasma proteins could contribute to chronic infection and inflammation.

Dataset Information

Multiple mechanisms allow Mycobacterium tuberculosis to continuously inhibit MHC class II-mediated antigen presentation by macrophages.

Publications

Multiple mechanisms allow Mycobacterium tuberculosis to continuously inhibit MHC class II-mediated antigen presentation by macrophages.

Similar Datasets

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