Computational Methods for Investigating Dendritic Cell Biology

Abstract

<p>The immune system is constantly faced with the daunting task of protecting the host from a large number of ever-evolving pathogens. In vertebrates, the immune response results from the interplay of two cellular systems: the innate immunity and the adaptive immunity. In the past decades, dendritic cells have emerged as major players in the modulation of the immune response, being one of the primary links between these two branches of the immune system.</p><p>Dendritic cells are pathogen-sensing cells that alert the rest of the immune system of the presence of infection. The signals sent by dendritic cells result in the recruitment of the appropriate cell types and molecules required for effectively clearing the infection. A question of utmost importance in our understanding of the immune response and our ability to manipulate it in the development of vaccines and therapies is: "How do dendritic cells translate the various cues they perceive from the environment into different signals that specifically activate the appropriate parts of the immune system that result in an immune response streamlined to clear the given pathogen?"</p><p>Here we have developed computational and statistical methods aimed to address specific aspects of this question. In particular, understanding how dendritic cells ultimately modulate the immune response requires an understanding of the subtleties of their maturation process in response to different environmental signals. Hence, the first part of this dissertation focuses on elucidating the changes in the transcriptional</p><p>program of dendritic cells in response to the detection of two common pathogen- associated molecules, LPS and CpG. We have developed a method based on Langevin and Dirichlet processes to model and cluster gene expression temporal data, and have used it to identify, on a large scale, genes that present unique and common transcriptional behaviors in response to these two stimuli. Additionally, we have also investigated a different, but related, aspect of dendritic cell modulation of the adaptive immune response. In the second part of this dissertation, we present a method to predict peptides that will bind to MHC molecules, a requirement for the activation of pathogen-specific T cells. Together, these studies contribute to the elucidation of important aspects of dendritic cell biology.</p>