Immune Programs and Related T Cell Mechanisms of Pulmonary Complications After COVID-19 Illness - SUMMARY
Patients who survive severe COVID-19 illness are at risk of developing pulmonary complications. While this may
resolve, some patients experience progression of their disease, resulting in severe lung damage. Although T
cells are critical to anti-viral responses in the lungs, sustained T-cell alterations in the blood after COVID-19
illness implicates them in persistent disease. There is a major knowledge gap regarding if, and how, circulating
T cells contribute to lung pathology. Our understanding is hampered by the variable clinical nature of pulmonary
disease, as well as the challenges to identifying pathogenic T cells in the blood and defining relationships to
disease course. The current project overcomes these barriers by applying innovative single-cell methods and
powerful machine learning tools that are exquisitely tailored to detect disease-relevant cell populations in the
blood, and to define the cellular and molecular dynamics that constitute immune programs governing pulmonary
complications of COVID-19. The study leverages a unique and highly characterized cohort of COVID-19 patients
defined by their severity of acute illness and developing fibrosis. By garnering data on hundreds of cellular and
molecular features in a large sample of patients, we are now poised to significantly advance the field. Preliminary
findings reveal pulmonary phenotypes that discriminate severe airway disease, and perturbations in discrete
CD4+ and CD8+ T-cell populations, including IFN-γ-producing virus-specific cells, related to these clinical
entities. A shared feature of T cells identified is their expression of T-bet, a transcription factor also expressed
by tissue-homing B cells that persist after COVID-19 illness. Further, our data support an interplay between these
T cells and B cells. Accordingly, we will test the overarching hypothesis that sustained perturbations in novel
CD4+ and CD8+ T cells expressing T-bet, including virus-specific cells, mark pro-fibrotic pulmonary phenotypes.
These cells create a persistent feedforward circuit of IFN-γ-dependent inflammation through coordinated actions
with B cells. First, immune programs of pulmonary disease will be defined and their trajectories mapped in
relation to progression and recovery on the basis of concerted T cells, other immune cells and inflammatory
mediators operating in vivo over 2 years. This will involve resolving protein signatures and gene expression
profiles of T cells at unprecedented depth to determine their functions and evolution (Aim 1). Next, the
contributions of epitope-specific T cells to divergent recovery paths will be distinguished in order to address how
progression and resolution is regulated by virus epitopes (Aim 2). To this end, a combinatorial tetramer method
will monitor the proportions and functions of up to 6 epitope specificities within each subject. Finally, we will
confirm the ability for pathogenic T cells from subjects with developing fibrosis, to synergize with T-bet+ B cells
by promoting IFN-γ-dependent inflammation in vitro, through a process involving a novel potential biomarker of
disease progression, CXCL13 (Aim 3). Assembling “elements of the T-cell puzzle” will identify mechanisms of
disease that reveal new therapeutic targets for halting or reversing lung inflammation after COVID-19 illness.
