The overall objective of the Ubiquitin Enzymes in Immunity & Disease (Ubi-ID) lab at the Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) is to expoit ubiquitin enzymes as new pharmacologic targets / tools for immune diseases. It is estimated that 20-30% of the current world’s population suffers from one or more allergic disorders representing a rising socioeconomic burden. Asthma is a chronic inflammatory disease of the lower airways that affects near 400 million people worldwide. Despite high diversity of endotypes characteristic of this pathology, half of asthmatic patients present a high Type-2 inflammation. It is well-established that Th2 lymphocytes represent a major source of Type 2 cytokines and are key drivers of asthma pathogenesis because of their myriad effects on both structural and inflammatory cells in the airways. Many of the therapeutic antibodies are targeting Type 2 cytokines and Type 2 cytokine receptors. Because Type 2 immunity helps to maintain immune homeostasis, it will be important to fine tune these therapies to avoid unwanted side effects. A precise understanding of the pathobiology of Type 2 diseases and of the underlying immunological mechanisms is therefore required to pave the way for effective drug development.

We have previously shown that the ASB2α E3 ubiquitin ligase in Th2 lymphocytes negatively regulates anti-tumor immunity in colorectal cancer and that loss of ASB2α in Th2 lymphocytes favors a Type 1 anti-tumor immune response (Spinner et al., Cancer Immunology Research 2019), but the molecular and cellular mechanisms whereby ASB2α exerts its effects to positively regulate Th2 lymphocyte function remained under investigated. In addition, whether ASB2α and its substrates represent prominent targets to mitigate type 2 responses in allergic diseases was unknown. Using unbiased large-scale approaches, we now show that filamins A and B are the only substrates of ASB2α in Th2 lymphocytes and that low levels of filamins A and B confer a specific elongated cell shape conducive to an α_Vβ₃ integrin-dependent dynamic migration.

Remarkably, genes encoding the α_V and β₃ integrin subunits and ASB2α harbor cis-regulatory regions that are specifically active in Th2 lymphocytes and belong to the core of Th2-specific genes, indicating a coordinated regulation of ASB2α and α_Vβ₃ integrin expression in Th2 lymphocytes to build an efficient Type 2 response. Accordingly, loss of ASB2α in Th2 lymphocytes reduces their recruitment in inflamed lungs and attenuates airway inflammation.

The innovative aspect of this work is not only to unravel a novel mechanism, the control of Th2 lymphocyte functions by the ASB2α-filamins A/B axis, but also to highlight an original target to mitigate Type 2 responses in asthma. In this context, it is worth mentioning that the ubiquitin system is amenable to pharmacological manipulation with small molecules. Because of their selectivity, E3 ubiquitin ligases are considered as therapeutic targets. Although biologics have recently made exciting strides in healthcare development, small molecules are still in the picture of innovative drug development. In contrast to the costly biologics, small molecules are more economically sustainable and more accessible to patients. Our results could potentially be important for therapeutics and companies interested in developing small compounds to modulate Type 2 immune responses.