Expansion of Cytotoxic CD4+ T cells in the lungs in severe COVID-19

Kaneko, N.; Boucau, J.; Kuo, H.-h.; Perugino, C.; Mahajan, V.; Farmer, J.; Liu, H.; Diefenbach, T.; Piechocka-Trocha, A.; Lefteri, K.; Waring, M.; Premo, K.; Walker, B.; Li, J. Z.; Gaiha, G.; Yu, X.; Lichterfeld, M.; Padera, R.; Pillai, S.

The contributions of T cells infiltrating the lungs to SARS-CoV-2 clearance and disease progression are poorly understood. Although studies of CD8+ T cells in bronchoalveolar lavage and blood have suggested that these cells are exhausted in severe COVID-19, CD4+ T cells have not been systematically interrogated within the lung parenchyma. We establish here that cytotoxic CD4+ T cells (CD4+CTLs) are prominently expanded in the COVID-19 lung infiltrate. CD4+CTL numbers in the lung increase with disease severity and progression is accompanied by widespread HLA-DR expression on lung epithelial and endothelial cells, increased apoptosis of epithelial cells and tissue remodeling. Based on quantitative evidence for re-activation in the lung milieu, CD4+ CTLs are as likely to drive viral clearance as CD8+ T cells and may also be contributors to lung inflammation and eventually to fibrosis in severe COVID-19.