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

ABSTRACT: 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.

SUBMITTER: Devenish LP

PROVIDER: S-EPMC8144502 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Proteins of the NACHT [NAIP (neuronal apoptosis inhibitory protein), CIITA (MHC class II transcription activator), HET-E (incompatibility locus protein from Podospora anserina) and TP1 (telomerase-associated protein)] family may serve as critical pathogen-sensing and signal-transducing molecules within the innate immune system. In the present paper, we show that CLAN [CARD (caspase-recruitment domain), LRR (leucine-rich repeat) and NACHT domain-containing protein], a NACHT-containing protein originally demonstrated to bind and activate pro-caspase 1, is also capable of influencing the functions of other members of the NACHT family. Through heterotypic NACHT-domain interactions, CLAN was found to associate with Nod1, Nod2 and NAC [nucleotide-binding domain and CARD-containing protein; NALP1 (NACHT, LRR and PYRIN protein 1)] when co-expressed in HEK-293T (human embryonic kidney) cells. NF-kappaB (nuclear factor kappaB) reporter assays demonstrated that co-expression of either full-length CLAN or the NACHT domain of CLAN significantly inhibited NF-kappaB activation induced by Nod1 or Nod2 overexpression. In addition, co-expression of CLAN or the NACHT domain of CLAN with Nod1 or Nod2 inhibited the ability of these proteins to generate active IL-1beta (interleukin 1beta) through their association with pro-caspase 1. The NACHT domain of CLAN was demonstrated by co-immunoprecipitation experiments to bind all NACHT domains that were tested, including the NACHT domains from CLAN itself, Nod1, Nod2, cryopyrin, NAC, PAN2 [PAAD [pyrin, AIM (absent-in-melanoma), ASC (apoptosis-associated speck-like protein containing a CARD) and death-domain-like]- and NACHT-containing protein] and NAIP (neuronal apoptosis inhibitory protein). Finally, monocyte-expressed CLAN was found to associate with Nod2 following exposure to bacterial peptidoglycan, implying a regulatory role for interaction of these NACHT proteins in the innate immune response. These studies suggest that by mediating hetero-oligomerization, NACHT domains provide a means by which various NACHT-containing proteins may interact, creating protein-interaction networks that potentially modulate immune responses to invading pathogens.

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

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