Upregulation of CCR4 in activated CD8(+) T cells indicates enhanced lung homing in patients with severe acute SARS‐CoV‐2 infection

Spoerl, Silvia; Kremer, Anita N.; Aigner, Michael; Eisenhauer, Nina; Koch, Pauline; Meretuk, Lina; Löffler, Patrick; Tenbusch, Matthias; Maier, Clara; Überla, Klaus; Heinzerling, Lucie; Frey, Benjamin; Lutzny‐Geier, Gloria; Winkler, Thomas H.; Krönke, Gerhard; Vetter, Marcel; Bruns, Heiko; Neurath, Markus F.; Mackensen, Andreas; Kremer, Andreas E.; Völkl, Simon

COVID‐19 is a life‐threatening disease leading to bilateral pneumonia and respiratory failure. The underlying reasons why a smaller percentage of patients present with severe pulmonary symptoms whereas the majority is only mildly affected are to date not well understood. Comparing the immunological phenotype in healthy donors and patients with mild versus severe COVID‐19 shows that in COVID‐19 patients, NK‐/B‐cell activation and proliferation are enhanced independent of severity. As an important precondition for effective antibody responses, T‐follicular helper cells and antibody secreting cells are increased both in patients with mild and severe SARS‐CoV‐2 infection. Beyond this, T cells in COVID‐19 patients exhibit a stronger activation profile with differentiation toward effector cell phenotypes. Importantly, when looking at the rates of pulmonary complications in COVID‐19 patients, the chemokine receptor CCR4 is higher expressed by both CD4 and CD8 T cells of patients with severe COVID‐19. This raises the hypothesis that CCR4 upregulation on T cells in the pathogenesis of COVID‐19 promotes stronger T‐cell attraction to the lungs leading to increased immune activation with presumably higher pulmonary toxicity. Our study contributes significantly to the understanding of the immunological changes during COVID‐19, as new therapeutic agents, preferentially targeting the immune system, are highly warranted.