CD4+ T cell signature in long COVID: insights from an unvaccinated cohort

By
Thiago Cerqueira-Silva
Benjamin Goodwin
Cíntia Araújo
Jessica J. Silva
Blenda de J. Pereira
Ícaro Bonyek Santos da Silva
Sara Nunes
Ananda Marinho
Ana Paula Barreto
Marcio Barreto
Marcelo Chalhoub
Juliana Ribeiro Caldas
Vishal Rao
Camila Coelho
Adolfo Rojas-Hidalgo
Vinicius Maracaja-Coutinho
Ricardo Khouri
Cristina R. Cardoso
Aldina Barral
Manoel Barral-Netto
Natalia Machado Tavares
Jennifer Dan
Viviane S. Boaventura
June 29, 2026
0 min

Frontiers In Immunology

Objective:

To determine the primary immunological footprint of Long COVID (LC) by examining a specific cohort that minimizes confounding factors such as vaccination and reinfection, focusing on CD4+ T cell responses.

Approach:

Cohort Analysis: Analyzed a Brazilian cohort of 104 patients, mostly unvaccinated, recruited between September 2020 and February 2021.
Immunological Assessment: Assessed humoral responses to SARS-CoV-2 and latent viruses, and investigated CD4+ T cell immune signatures in a subset of 6 LC and 4 recovered control (RC) patients.
Techniques Used: Utilized flow cytometry and single-cell RNA sequencing for immune signature analysis.

Key Findings:

Systemic humoral responses to SARS-CoV-2 and reactivated latent viruses were comparable between LC and RC groups.
Distinct immune signatures were observed in LC patients, characterized by acute activation of CD4+ T cells.
Increased expression of interferon-alpha/gamma signatures was noted in LC patients compared to RC.
No evidence of clonal expansion in the T cell receptor repertoire was found.

Interpretation:

The findings indicate a qualitative T cell dysfunction characterized by CD4+ non-proliferative activation in LC patients.

Limitations:

The study focused on a small subset of patients for detailed immune analysis.
Findings may not be generalizable beyond the specific cohort of unvaccinated individuals.