Understanding molecular mechanisms of T-helper 17 differentiation

Abstract

Pro-inflammatory Th17 cells are critical for mucosal immune responses and also have implications in development of autoimmune disorders. So far, Th17 regulatory networks have been investigated using mouse models, but the human counterpart is largely unexplored. This thesis is focused on elucidating the molecular mechanisms that dictate human Th17 differentiation. By studying early proteomic changes in human Th17 cells using mass-spectrometry, we have identified novel, potential regulators of the lineage. Strikingly, our findings discover significant dissimilarities in human and mouse Th17 proteomes. As a part of this study, we have further investigated the involvement of multiple AP-1 transcription factors in orchestrating the Th17 fate. Using functional genomics approaches in combination with genome-wide binding analysis, we have investigated the species-specific roles of these factors along with their characteristic functional interplay and potential mechanism of action. Our findings provide crucial insights into the development of Th17-associated pathologies and underscore the fact that though molecular paradigms are largely conserved between human and mouse, there are subtle differences which need to be acknowledged. Understanding them is vital for designing immunotherapeutic measures.