T cell activation depends on Ca2+ signals after activation of the T cell receptor (TCR), regulating many aspects such as gene expression, cytokine production, metabolism, and proliferation. Influx upon antigen binding to the TCR is mediated by the highly selective release-activated Ca2+ channel (CRAC) in the plasma membrane.
A study from the University of New York (USA) investigated human cells’ use of charged particles, mainly calcium, to send signals and activate biological switches. When activated, whether by viral proteins or allergens, T cells open channels in their outer membranes, letting calcium rush in to activate signalling pathways that control cell division and the secretion of cytokine molecules that help T cells.
Experiments showed that deletion of a calcium channel gene (CRAC) formed by ORAI1-proteins significantly reduced asthmatic inflammation in the lungs of mice caused by house dust mite faeces, a common cause of the disease.
The report provides evidence that a new class of drugs targeting CRAC channels can be safely used to counteract allergic asthma without creating vulnerability to infection. Its systemic application specifically suppressed airway inflammation in response to allergen exposure.
According to the study, allergic asthma is characterized by increased type 2 (T2) inflammation, which involves a subset of T cells called T helper (Th) 2 cells. Th2 cells produce cytokines that play a vital role in normal immune defences and disease-causing inflammation that occurs in the wrong place and the wrong amount. The cytokines promote the production of a type of antibody called IgE and the recruitment to the lungs of inflammation-causing immune cells called eosinophils, the hallmarks of the disease.
The research team found that genetic suppression of ORAI1 in T cells, or treatment of mice with the CRAC channel inhibitor CM4620, completely suppressed Th2-driven airway inflammation in response to dust mite allergens. House dust. CM4620 is in Phase 2 clinical trials for COVID-19-associated lung inflammation and acute pancreatitis.
CM4620 treatment significantly reduced airway inflammation compared to an inactive control substance, and the treated mice also showed much lower levels of Th2 cytokines and related gene expression. According to the authors, without calcium influx through CRAC channels, T cells cannot become Th2 cells and produce the cytokines that cause disease.
In contrast, suppression of the ORAI1 gene, or interference with the function of CRAC channels on T cells by the study drug, did not impair T cell-driven antiviral immunity, as pulmonary inflammation and responses immune responses were similar in mice with and without ORAI1.
The work demonstrates that Th2-mediated airway inflammation depends more on CRAC channels than on T-cell-mediated antiviral immunity in the lung. This suggests that inhibition of CRAC channels is a promising future therapeutic approach for allergic airway disease.
