Multiple mechanisms allowMycobacterium tuberculosisto 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.antigen processing ͉ mathematical model ͉ HLA ͉ cell-mediated immunity

Francisella tularensisInduces Ubiquitin-Dependent Major Histocompatibility Complex Class II Degradation in Activated Macrophages

“…If the PGE 2 in the LVS infection supernatant was the only molecule responsible for class II downregulation by the established mechanism of eliciting cyclic AMP-induced protein kinase A (PKA) activation and subsequent CIITA phosphorylation and inhibition (33), this would not be expected to result in a Ͼ70% inhibition of MHC class II protein expression in 12 h. This finding is consistent with mathematic modeling studies that indicate it would require Ͼ10 h to observe a decrease in class II expression after a block in mRNA translation (8) and suggests the presence of an additional factor in the F. tularensis BMDM supernatants that is eliciting macrophage MHC class II downregulation via a distinct mechanism.…”

Mycobacterium bovis BCG Attenuates Surface Expression of Mature Class II Molecules through IL-10-Dependent Inhibition of Cathepsin S

“…Defective expression of IFN-␥-induced MHC class II molecules in macrophages infected with pathogenic mycobacteria has been studied extensively and has been shown to involve multiple mechanisms (44). For example, using the RAW 264.7 mouse macrophage cell line infected with M. avium as a model, reduced surface expression of class II proteins was shown to be associated with inhibition of IFN-␥ signaling and STAT-1 phosphorylation and MHC class II gene expression (45).…”

A comparison of random vs. chemotaxis-driven contacts of T cells with dendritic cells during repertoire scanning

“…Time dependent correlations can also be identified. We have used this approach to identify key parameters in ODE models (e.g., (Chang et al, 2005;Marino and Kirschner, 2004;Sud et al, 2006;Wigginton and Kirschner, 2001). In addition, we have adapted this approach, originally developed for ODEs, for use in agent-based model setting (Marino et al, submitted 2007;Segovia-Juarez et al, 2004) To explore effects of uncertainty in our model, we used a C program to create a Latin Hypercube Sampling (LHS) (Blower and Dowlatabadi, 1994;Blower et al, 2000;Helton and Davis, 2003) of our parameter values.…”