LA JOLLA, CA— Allergic asthma is a chronic inflammatory disease of the lung and airways driven, at least in part, by, a subgroup of overly active T helper cells. Thus, to devise better treatments, it is essential to determine how this cell population, known as TH2 cells, develops, matures and then crosses the line between protection and tissue damage.
These questions are the subject of a new study published online in the June 20, 2018 edition of Nature Immunology from the laboratory of La Jolla Institute for Immunology (LJI) professor Yun-Cai Liu, Ph.D. The paper reports that allergy-associated TH2 populations develop in mice genetically engineered to lack two enzymes—known as Itch and WWP2—whose normal job is to decorate other proteins with the small molecule ubiquitin to regulate protein function in cells.
The study found that the pair’s activity converges on a known regulator of immune activity and shows that mice lacking both Itch and WWP2 develop severe lung inflammation. These discoveries could be exploited in novel strategies to treat asthma.
But Liu cautions that “wiping out this TH2 cell population as a means to counter asthma is not a treatment option since their normal job of is to defend cells against parasitic invasion.” Instead, researchers hope to define genetic pathways that regulate immune activity and then intervene where things go awry.
The new paper suggests one such point of intervention. The authors identify SHP-1, a known regulator of immune signaling, as the target protein likely to be simultaneously ubiquitinated by both Itch and WWP2 in TH2 cells. Additional experiments supported the idea that ubiquitinated SHP-1 is what puts the molecular brakes on TH2 cell hyperactivation, not SHP-1 devoid of modification.
“A very important contribution of our study is to reveal the regulatory circuit whereby Itch and WWP2 control T cell signaling and differentiation,” says Daisuke Aki, Ph.D., a senior postdoctoral fellow in Liu’s lab and the study’s lead author. “Moreover, SHP-1 has potential as an attractive drug target to treat allergic diseases such as human asthma.”
Liu’s lab has a historic interest in how protein ubiquitination regulates immune responses. He previously reported that genetic inactivation of the aptly named Itch inappropriately activated T cells in mice and promoted asthma. Others had previously implicated Itch in inflammatory skin disease as some Itch-mutant mice excessively scratch themselves. Given that loss of Itch provokes inflammation, Liu’s group reasoned that Itch, or its structurally similar cousin WWP2, might be protective against these conditions.
To determine this, Liu’s group, working both at LJI and the Institute of Immunology at Tsinghua University in Beijing, genetically engineered mice to lack Itch, WWP2 or both proteins in T cells. Genetic and biochemical analysis of each mouse group supported the “synergy” thesis: double mutant mice spontaneously developed severe lung inflammation and showed lung tissue damage, to an extent not observed in Itch or WWP2 single-mutant mice.
Moreover, double-mutant mice exhibited classic hallmarks of autoimmunity, such as elevated serum levels of pro-inflammatory cytokines and anti-self antibodies, again to a greater extent than did single-mutant mice. These outcomes confirm that mice lacking both genes lose their normal protection against autoimmune responses. “Since Itch mutations are involved in human multisystem autoimmune diseases, the double mutant mice could be a good animal model to mimic human situations,” says Liu.
The team also performed experiments showing that Itch and WWP2 proteins interact in a complex inside cells. “These observations strongly indicate a functional collaboration between these two enzymes that add ubiquitin to proteins in controlling T cell development and limiting the number of TH2 cells.” says Aki.
They then conducted experiments supporting the idea that ubiquitinated SHP-1 is what puts the molecular brakes on TH2 cell hyperactivation, not SHP-1 devoid of modification.
This work was supported primarily by the National Science Foundation of China and the National Institutes of Health, USA.
Daisuke Aki, Hui Li, Wen Zhang, Mingke Zheng, Chris Elly, Jee H. Lee, Weiguo Zou, and Yun-Cai Liu. The E3 ligases Itch and WWP2 cooperate to limit TH2 differentiation by enhancing signaling through the TCR. Nat Immunol, 2018. doi: 10.1038/s41590-018-0137-8
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The La Jolla Institute for Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading toward its goal: life without disease.