Heterogeneity of the T & NK cell microenvironment in PBMCs and BALF from critical patients with COVID-19

Numerous single-cell RNA sequencing (scRNA-seq) studies have been conducted in the field of COVID-19 immunology, with a predominant focus on peripheral blood mononuclear cells (PBMCs). In contrast, longitudinal investigations of the pulmonary microenvironment have posed substantial clinical and technical challenges. Here, we independently constructed longitudinal cellular landscapes of T and natural killer (NK) cells in both PBMCs and bronchoalveolar lavage fluid (BALF) compartments derived from critical patients with COVID-19. To this end, we developed a computational framework that leverages cell frequency dynamics over the recovery trajectory to identify heterogeneous immune signatures of T and NK cells in PBMCs and BALF. Notably, Th2 cells in BALF (bTh2) exhibited a Th1-like response signature associated with patient recovery, whereas dysfunctional Th1 cells in BALF (bTh1) were associated with mortality–yet such association was not detected in PBMCs. Protective CD8 + T effector cells characterized by high KLRG1 expression in BALF also contributed to the recovery of COVID-19 patients. Furthermore, we identified a putative interaction between bTh2 cells and CD8 + T effector cells via the TNFSF14 axis, which may promote patient survival. Collectively, our findings offer cellular and molecular insights that may inform the future development of precision medicine strategies for patients critical COVID-19.