The effects of Mycobacterium tuberculosis on T cell responsiveness in granulomas

Background:
The pathologic hallmark of infection with Mycobacterium tuberculosis (Mtb) are granulomas, collections of host immune cells (e.g. macrophages and T cells) that organize in an attempt to contain and eliminate the infection. Since granulomas are the sites of infection within lungs, we expect them to be enriched substantially in Mtb-responsive T cells (producing cytokines in response to Mtb). Surprisingly, a low frequency of Mtb-responsive T cells (~ 10%) in granulomas have been observed. As Mtb-specific T cells are key to clearance of the pathogen, it is important to determine why the frequency of functional T cells in granulomas is so low. One hypothesis is that T cells are being down-regulated directly by Mtb.

Methods:
To study this dynamic, we use a Multi-Scale Modeling (MSM) approach. Our lab has previously created an agent-based model (ABM), known as GranSim, that tracks bacteria as individual immune cells as agents. In addition, we have an existing system of ODEs that captures Mtb-mediated down-regulation of MHCII presentation of peptides in macrophages that we have previously published. We create a novel hybrid, multi-scale computational model by linking these two models putting these equations directly into antigen presenting cells within GranSim resulting in a MSM that spans scales from intracellular to tissue.

Results:
In this study, we found mid range down regulation of MHC II transcription was most advantageous for Mtb growth, however, down regulation of MHC II maturation lowered T cell response.

Discussion:
This work provides insights into mechanisms that could be either enhanced or inhibited to therapeutically increase frequencies of Mtb-responsive T cells and at the same to helping to understand what mechanisms may be contributing to the extremely low levels of responsiveness.