Profound Treg perturbations correlate with COVID-19 severity

Galván-Peña, Silvia; Leon, Juliette; Chowdhary, Kaitavjeet; Michelson, Daniel A.; Vijaykumar, Brinda; Yang, Liang; Magnuson, Angela; Manickas-Hill, Zachary; Piechocka-Trocha, Alicja; Worrall, Daniel P.; Hall, Kathryn E.; Ghebremichael, Musie; Walker, Bruce D.; Li, Jonathan Z.; Yu, Xu G.; Mathis, Diane; Benoist, Christophe

The hallmark of severe COVID-19 disease has been an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We explored the hypothesis that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in both Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, which correlated with poor outcomes. Accordingly, these Tregs over-expressed a range of suppressive effectors, but also pro-inflammatory molecules like IL32. Most strikingly, they acquired similarity to tumor-infiltrating Tregs, known to suppress local anti-tumor responses. These traits were most marked in acute patients with severe disease, but persisted somewhat in convalescent patients. These results suggest that Tregs may play nefarious roles in COVID-19, via suppressing anti-viral T cell responses during the severe phase of the disease, and/or via a direct pro-inflammatory role.