Guy T¹, Gadiraju CV¹, Stone JH², Perugino C², Mahajan VS¹, Pillai S¹

¹Ragon Institute of MGH, MIT and Harvard, Boston MA; ²Massachusetts General Hospital, Boston, MA

There has been growing interest in the role of cytotoxic CD4+ T cells (CD4-CTLs) in human health and disease. 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. Granzyme K and granzyme B are key mediators produced by different CD4-CTL populations. It has recently been suggested that granzyme K may drive complement activation through a novel pathway. Severe disease in IgG4-RD is associated with hypocomplementemia, however the mechanism is unclear.

 

We have performed a multiomic analysis on granzyme K+ and granzyme B+ CD4 T+ cells in a number of acute and chronic disease contexts and identified strong links between granzyme K and complement activation in IgG4-RD. By understanding the key developmental pathways and function of CD4-CTLs in human disease, we may next 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.