Abstract Text: There has been growing interest in the role of cytotoxic CD4+ T cells (CD4-CTLs) in human health and disease over the past decade. While commonly observed in patients with cancer and autoimmune conditions such as IgG4-related disease (IgG4-RD), they are also expanded in healthy supercentenarians and have been recently characterised in acute conditions including severe acute respiratory syndrome coronavirus 2 2019 (SARS-CoV-2) infection. Importantly, in patients with severe SARS-CoV-2 infection they are associated with bias away from protective antibody production. While a significant body of work has been done to understand these cells, there are still many questions about their developmental pathways, function and significance in a number of human diseases.
To better understand these cells and how they influence adaptive immunity, we performed RNA sequencing, whole genome bisulfite sequencing (WGBS) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) on FACs sorted CD4-CTLs, CD8-CTLs, Th1 CD4 cells, naive CD4 and CD8 T cells from the peripheral blood of patients with IgG4-RD and idiopathic pulmonary fibrosis. We have identified key epigenetic and transcriptional signatures associated with CD4-CTLs that help elucidate their development and provide insights into their roles in the adaptive immune system. Functional studies in mouse models are currently being performed to confirm molecular mechanisms.
By understanding the key developmental pathways and function of CD4-CTLs in human disease, we may be able to manipulate their impact on adaptive immune responses to improve vaccine development and antitumor therapeutics, as well as limit their role in autoimmune and inflammatory conditions.
