The essential roles of helper T lymphocyte in inflammation

Th17 and Treg cells are subsets of T helper cells, with pro- and anti-inflammatory roles, and they regulate each other creating a balance in the immune system. STAT3 is an important transcription factor for the development and cytokine production of Th17 cells. Loss-of-function mutations in STAT3 can impair its function and create severe immunological complications. PSMB5, a proteosome subunit, was previously shown to be differentially expressed in murine Th17 and Treg cells, suggesting a regulatory role in these cell subsets. Disturbance of the proteasome may lead to protein changes that affect the immune response by altering the Th17/Treg balance. T cells are also involved in infectious diseases, such as COVID-19, caused by SARS-CoV-2. The progression and severity of COVID-19 are influenced by key factors such as the presence of comorbidities. Despite interpatient heterogeneity of medical conditions, there could be key signature proteins which determine the underlying immune responses in COVID-19 patients with comorbidities. We studied the impact of a novel STAT3 mutation discovered in a patient with recurrent pulmonary aspergillosis, and her asymptomatic family members. Transcriptomic analysis demonstrated that the presence of the infection in the patient was related to the downregulation of Th17 and Th1, and the upregulation of Treg markers, impairing the defense capacity of the immune system. Changes in Th17 and Treg cells were also observed in one of the asymptomatic family members. Furthermore, we characterized the effect of targeting PSMB5 in the differentiation of Th17 and Treg cells. The inhibition of PSMB5 led to an increase in Th17 markers and a decrease in Treg markers. Decreased glycolysis was observed in Th17, and increased mTORC2 levels in Treg cells. This suggests a change to immunosuppressive role of the Th17 cells, and disruption in FOXP3 stability and suppressive activity in the Treg cells. Moreover, proteomics approaches were used to investigate protein changes in the plasma of COVID-19 patients with or without general comorbidities. Among the differences observed, the levels of soluble CD4 were increased and IL17 signaling pathway reduced when comparing COVID-19 patients with comorbidities to healthy and disease controls, respectively. In conclusion, this project identified key mechanisms contributing to the Th17/Treg balance.

Keywords: COVID-19, immunology, proteasome, PSMB5, regulatory T cell, SARS-CoV-2, STAT3, T helper 17, T lymphocyte