Absent in Melanoma 2 (AIM2) Regulates the Stability of Regulatory T Cells.

Beatriz Lozano-Ruiz,David Moreno,José M González-Navajas,Rubén Francés,Amalia Tzoumpa,Ana R Cortazar,Gloria Peiró,Claudia Martínez-Cardona,Joanna Picó,Juanjo Lozano,Ana M Aransay,Pedro Zapater

doi:10.3390/ijms23042230

Abstract

Absent in melanoma 2 (AIM2) is a cytosolic dsDNA sensor that has been broadly studied for its role in inflammasome assembly. However, little is known about the function of AIM2 in adaptive immune cells. The purpose of this study was to investigate whether AIM2 has a cell-intrinsic role in CD4+ T cell differentiation or function. We found that AIM2 is expressed in both human and mouse CD4+ T cells and that its expression is affected by T cell receptor (TCR) activation. Naïve CD4+ T cells from AIM2-deficient (Aim2−/−) mice showed higher ability to maintain forkhead box P3 (FOXP3) expression in vitro, while their capacity to differentiate into T helper (Th)1, Th2 or Th17 cells remained unaltered. Transcriptional profiling by RNA sequencing showed that AIM2 might affect regulatory T cell (Treg) stability not by controlling the expression of Treg signature genes, but through the regulation of the cell’s metabolism. In addition, in a T cell transfer model of colitis, Aim2−/−-naïve T cells induced less severe body weight loss and displayed a higher ability to differentiate into FOXP3+ cells in vivo. In conclusion, we show that AIM2 function is not confined to innate immune cells but is also important in CD4+ T cells. Our data identify AIM2 as a regulator of FOXP3+ Treg cell differentiation and as a potential intervention target for restoring T cell homeostasis.

Highlights

Absent in melanoma 2 (AIM2) is a cytosolic receptor that senses dsDNA from any origin, including viruses, bacteria and self-dsDNA [1–3]. It was originally identified as a tumor suppressor in melanoma [4], most of the research conducted on AIM2 has focused on its function in inflammasome activation and innate immune defense against intracellular pathogens [5]
In addition to AIM2, various pattern recognition receptors can induce the assembly of the inflammasome complex, including several members of the NOD-like receptor (NLR) family, the AIM2-like receptor known as interferon-γ (IFNγ)-inducible protein 16 (IFI16), and the protein Pyrin [8,9]
AIM2 Expression in CD4+ T Cells Is Controlled by T cell receptor (TCR) Activation

Summary

Introduction

Absent in melanoma 2 (AIM2) is a cytosolic receptor that senses dsDNA from any origin, including viruses, bacteria and self-dsDNA [1–3] It was originally identified as a tumor suppressor in melanoma [4], most of the research conducted on AIM2 has focused on its function in inflammasome activation and innate immune defense against intracellular pathogens [5]. Each of these receptors is activated by different stimuli, from microbial components to signs of cellular disturbance or damage Among all these receptors, the NLRP3 (NLR family, pyrin domain containing 3) is the prototypical and most thoroughly studied inflammasome. The NLRP3 (NLR family, pyrin domain containing 3) is the prototypical and most thoroughly studied inflammasome Once they are activated, the majority of these receptors, including AIM2 and NLRP3, require the adaptor protein ASC (apoptosis-associated specklike protein, containing a caspase recruitment domain) to recruit caspase-1 and initiate full inflammasome assembly [10]. The adaptor ASC has been reported to play a critical

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