Immune Regulation in Time and Space: The Role of Local- and Long-Range Genomic Interactions in Regulating Immune Responses

Mammals face and overcome an onslaught of endogenous and exogenous challenges in order to survive. Typical immune cells and barrier cells, such as epithelia, must respond rapidly and effectively to encountered pathogens and aberrant cells to prevent invasion and eliminate pathogenic species before they become overgrown and cause harm. On the other hand, inappropriate initiation and failed termination of immune cell effector function in the absence of pathogens or aberrant tissue gives rise to a number of chronic, auto-immune, and neoplastic diseases. Therefore, the fine control of immune effector functions to provide for a rapid, robust response to challenge is essential. Importantly, immune cells are heterogeneous due to various factors relating to cytokine exposure and cell-cell interaction. For instance, tissue-resident macrophages and T cells are phenotypically, transcriptionally, and functionally distinct from their circulating counterparts. Indeed, even the same cell types in the same environment show distinct transcription patterns at the single cell level due to cellular noise, despite being robust in concert. Additionally, immune cells must remain quiescent in a naive state to avoid autoimmunity or chronic inflammatory states but must respond robustly upon activation regardless of their microenvironment or cellular noise. In recent years, accruing evidence from next-generation sequencing, chromatin capture techniques, and high-resolution imaging has shown that local- and long-range genome architecture plays an important role in coordinating rapid and robust transcriptional responses. Here, we discuss the local- and long-range genome architecture of immune cells and the resultant changes upon pathogen or antigen exposure. Furthermore, we argue that genome structures contribute functionally to rapid and robust responses under noisy and distinct cellular environments and propose a model to explain this phenomenon.