Persistent CD8+ T cell proliferation and activation in COVID-19 adult survivors with post-acute sequelae: a longitudinal, observational cohort study of persistent symptoms and T cell markers

Stephanie M LaVergne; Taru S Dutt; Kim McFann; Bridget A Baxter; Tracy L Webb; Kailey Berry; Maddy Tipton; Sophia Stromberg; Brian M Sullivan; Julie Dunn; Marcela Henao-Tamayo; Elizabeth P Ryan

doi:10.3389/fimmu.2023.1303971

Persistent CD8⁺ T cell proliferation and activation in COVID-19 adult survivors with post-acute sequelae: a longitudinal, observational cohort study of persistent symptoms and T cell markers

Front Immunol. 2024 Jan 23:14:1303971. doi: 10.3389/fimmu.2023.1303971. eCollection 2023.

Authors

Affiliations

¹ Department of Environmental Radiological and Health Sciences, Colorado State University, Fort Collins, CO, United States.
² Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, United States.
³ University of Colorado Health, Medical Center of the Rockies, Loveland, CO, United States.
⁴ Department of Clinical Sciences, Colorado State University, Fort Collins, CO, United States.
⁵ Department of Molecular, Cellular, and Integrative Neurosciences, Colorado State University, Fort Collins, CO, United States.
⁶ Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, United States.
⁷ Department of Immunology and Microbiology, Scripps Research, La Jolla, CA, United States.

^# Contributed equally.

Abstract

Introduction: Post-acute sequelae of COVID-19 affects the quality of life of many COVID-19 survivors, yet the etiology of post-acute sequelae of COVID-19 remains unknown. We aimed to determine if persistent inflammation and ongoing T-cell activation during convalescence were a contributing factor to the pathogenesis of post-acute sequelae of COVID-19.

Methods: We evaluated 67 individuals diagnosed with COVID-19 by nasopharyngeal polymerase chain reaction for persistent symptoms during convalescence at separate time points occurring up to 180 days post-diagnosis. Fifty-two of these individuals were evaluated longitudinally. We obtained whole blood samples at each study visit, isolated peripheral blood mononuclear cells, and stained for multiple T cell activation markers for flow cytometry analysis. The activation states of participants' CD4⁺ and CD8⁺ T-cells were next analyzed for each of the persistent symptoms.

Results: Overall, we found that participants with persistent symptoms had significantly higher levels of inflammation at multiple time points during convalescence when compared to those who fully recovered from COVID-19. Participants with persistent dyspnea, forgetfulness, confusion, and chest pain had significantly higher levels of proliferating effector T-cells (CD8⁺Ki67⁺), and those with chest pain, joint pain, difficulty concentrating, and forgetfulness had higher levels of regulatory T-cells (CD4⁺CD25⁺). Additionally, those with dyspnea had significantly higher levels of CD8⁺CD38⁺, CD8⁺ Granzyme B⁺, and CD8⁺IL10⁺ cells. A retrospective comparison of acute phase inflammatory markers in adults with and without post-acute sequelae of COVID-19 showed that CD8⁺Ki67⁺ cells were significantly higher at the time of acute illness (up to 14 days post-diagnosis) in those who developed persistent dyspnea.

Discussion: These findings suggest continued CD8+ T-cell activation following SARS-CoV-2 infection in adults experiencing post-acute sequelae of COVID-19 and that the increase in T regulatory cells for a subset of these patients represents the ongoing attempt by the host to reduce inflammation.

Keywords: CD8+ T cell; COVID-19; SARS-CoV-2; cytotoxic T cells; post-COVID; post-acute sequelae of COVID-19.

Publication types

Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Adult
CD3 Complex
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
COVID-19* / complications
Cell Proliferation
Chest Pain
Cohort Studies
Convalescence
Disease Progression
Dyspnea
Humans
Inflammation
Ki-67 Antigen
Leukocytes, Mononuclear
Post-Acute COVID-19 Syndrome
Quality of Life
Retrospective Studies
SARS-CoV-2
Survivors

Substances

Ki-67 Antigen
CD3 Complex

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Provided by ER in the CSU Department of Environmental and Radiological Health Sciences in collaboration with JD and the Medical Center of the Rockies Trauma Research Department. Additional support was granted from the Poudre Valley Health Foundation for the clinical recruitment in the local hospitals.