Thymic tuft cells: potential "regulators" of non-mucosal tissue development and immune response.

As the leading central immune organ, the thymus is where T cells differentiate and mature, and plays an essential regulatory role in the adaptive immune response. Tuft cells, as chemosensory cells, were first found in rat tracheal epithelial, later gradually confirmed to exist in various mucosal and non-mucosal tissues. Although tuft cells are epithelial-derived, because of their wide heterogeneity, they show functions similar to cholinergic and immune cells in addition to chemosensory ability. As newly discovered non-mucosal tuft cells, thymic tuft cells have been demonstrated to be involved in and play vital roles in immune responses such as antigen presentation, immune tolerance, and type 2 immunity. In addition to their unique functions in the thymus, thymic tuft cells have the characteristics of peripheral tuft cells, so they may also participate in the process of tumorigenesis and virus infection. Here, we review tuft cells' characteristics, distribution, and potential functions. More importantly, the potential role of thymic tuft cells in immune response, tumorigenesis, and severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) infection was summarized and discussed.

Emerging Paradigms in Type 2 Immunity.

A principal purpose of type 2 immunity was thought to be defense against large parasites, but it also functions in the restoration of homeostasis, such as toxin clearance following snake bites. In other cases, like allergy, the type 2 T helper (Th2) cytokines and cells present in the environment are detrimental and cause diseases. In recent years, the recognition of cell heterogeneity within Th2-associated cell populations has revealed specific functions of cells with a particular phenotype or gene signature. In addition, here we discuss the recent data regarding heterogeneity of type 2 immunity-related cells, as well as their newly identified role in a variety of processes ranging from involvement in respiratory viral infections [especially in the context of the recent COVID-19 (coronavirus disease 2019) pandemic] to control of cancer development or of metabolic homeostasis.

Dupilumab use is associated with protection from COVID-19 mortality: A retrospective analysis.

We previously found that type 2 immunity promotes COVID-19 pathogenesis in a mouse model. To test relevance to human disease we used electronic health record databases and determined that patients on dupilumab (anti-IL-4R monoclonal antibody that blocks IL-13 and IL-4 signaling) at the time of COVID-19 infection had lower mortality.

Type 2 Immunity and Its Impact on COVID-19 Infection in the Airways.

Type 2 immune responses are characterized by elevated type 2 cytokines and blood eosinophilia. Emerging evidence suggests that people with chronic type 2 inflammatory lung diseases are not particularly susceptible to SARS-CoV-2 infection. Intriguingly, recent in vitro, ex vivo research demonstrates type 2 cytokines, particularly IL-13, reduce the risk of SARS-CoV-2 infection in the airway epithelium. IL-13 treatment in airway epithelial cells followed by SARS-CoV-2 diminished viral entry, replication, spread, and cell death. IL-13 reduces the expression of the angiotensin-converting enzyme 2 (ACE2) receptor in the airway epithelium and transmembrane serine protease 2 (TMPRSS2), particularly in ciliated cells. It also alters the cellular composition toward a secretory-cell-rich phenotype reducing total ciliated cells and, thus, reducing viral tropism. IL-13 enhances Muc5ac mucin and glycocalyx secretion in the periciliary layer, which acts as a physical barrier to restrict virus attachment. Moreover, type 2 airway immune cells, such as M2 alveolar macrophages, CD4+ tissue-resident memory T cells, and innate lymphoid 2 cells, may also rescue type 2 airways from SARS-CoV-2-induced adverse effects. In this review, we discuss recent findings that demonstrate how type 2 immunity alters immune responses against SARS-CoV-2 and its consequences on COVID-19 pathogenesis.

Safety and Efficacy of Dupilumab for the Treatment of Hospitalized Patients With Moderate to Severe Coronavirus Disease 2019: A Phase 2a Trial.

Background: Based on studies implicating the type 2 cytokine interleukin 13 (IL-13) as a potential contributor to critical coronavirus disease 2019 (COVID-19), this trial was designed as an early phase 2 study to assess dupilumab, a monoclonal antibody that blocks IL-13 and interleukin 4 signaling, for treatment of inpatients with COVID-19. Methods: We conducted a phase 2a randomized, double-blind, placebo-controlled trial (NCT04920916) to assess the safety and efficacy of dupilumab plus standard of care vs placebo plus standard of care in mitigating respiratory failure and death in those hospitalized with COVID-19. Results: Forty eligible subjects were enrolled from June to November of 2021. There was no statistically significant difference in adverse events nor in the primary endpoint of ventilator-free survival at day 28 between study arms. However, for the secondary endpoint of mortality at day 60, there were 2 deaths in the dupilumab group compared with 5 deaths in the placebo group (60-day survival: 89.5% vs 76.2%; adjusted hazard ratio [HR], 0.05 [95% confidence interval {CI}, .004-.72]; P = .03). Among subjects who were not in the intensive care unit (ICU) at randomization, 3 subjects in the dupilumab arm were admitted to the ICU compared to 6 in the placebo arm (17.7% vs 37.5%; adjusted HR, 0.44 [95% CI, .09-2.09]; P = .30). Last, we found evidence of type 2 signaling blockade in the dupilumab group through analysis of immune biomarkers over time. Conclusions: Although the primary outcome of day 28 ventilator-free survival was not reached, adverse events were not observed and survival was higher in the dupilumab group by day 60. Clinical Trials Registration: NCT04920916.