Immune dysregulation in long COVID patients uncovered in new study

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In a recent study published in the journal Nature Immunology, a team of scientists attempted to understand the etiology of long coronavirus disease (long COVID) using blood samples from patients with and without clear long COVID clinical trajectories and examining the immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through ‘omics’ approaches and serological assays.

Letter: Long COVID manifests with T cell dysregulation, inflammation and an uncoordinated adaptive immune response to SARS-CoV-2. Image Credit: p.ill.i / ShutterstockLetter: Long COVID manifests with T cell dysregulation, inflammation and an uncoordinated adaptive immune response to SARS-CoV-2. Image Credit: p.ill.i / Shutterstock


The spread and severity of the coronavirus disease 2019 (COVID-19) pandemic have been controlled through concerted efforts worldwide to develop vaccines against SARS-CoV-2 and vaccinate large portions of the global population. Emergent variants do not appear to have morbidity and mortality rates similar to those of the initial wave of COVID-19. However, long COVID, or post-acute sequelae of COVID-19 (PASC), continues to be a significant health concern, with persistent symptoms such as fatigue, myalgia, dyspnea, and long-term impacts on cardiovascular, neurological, and muscular health.

Recent studies on long COVID indicate that immune perturbations caused by the SARS-CoV-2 infection could be responsible for the long-term conditions. However, although 10% or more SARS-CoV-2 infections result in long COVID, the etiology and pathophysiology continue to remain unclear. Furthermore, while the role of T cells in the pathogenesis of and immunity against SARS-CoV-2 is known, the involvement of T cells in the development of long COVID is yet to be fully understood.

About the study

In the present study, the researchers used serological assays and an ‘omics’ approach to understand and characterize global immunity and specific immunity against SARS-CoV-2 using blood samples from patients with and without clinical manifestations of long COVID. They aimed to detect and characterize the immune features specifically associated with long COVID to understand the pathological mechanisms of the disease.

The study used cytometry by time of flight (CyTOF) serological assay, plasma proteomics, ribonucleic acid (RNA) sequencing, and single-cell RNA sequencing (scRNAseq) to characterize the phenotype of T cells in matched cohorts of COVID-19 patients with long COVID and patients who had completely recovered. Blood samples were obtained from a cohort of well-characterized COVID-19 patients eight months after the SARS-CoV-2 infection but before reinfection or COVID-19 vaccination.

Cryopreserved blood samples were analyzed once at baseline and again after they were stimulated using SARS-CoV-2 spike proteins to identify anti-SARS-CoV-2 T-cells using cytokine staining. The expression of a wide range of effector cells, including interferon-γ, numerous interleukins, tumor necrosis factor (TNF), and cytolytic markers such as perforin and granzyme B, were assessed for these T cells. Manual gating was used to identify specific types of T cells, such as naive, central memory, translational memory, effector memory, and stem cell memory T cells.

The expression levels of CyTOF markers such as human leukocyte antigen – DR isotype (HLA-DR), cluster of differentiation (CD) 13, CD29, CD38, and C-X-C chemokine receptor type 4 (CXCR-4), were also evaluated. The overexpression of specific genes involved in carbon dioxide transport and heme synthesis was also analyzed using RNA sequencing and scRNAseq methods. Additionally, plasma proteomic analyses were conducted to determine if immune regulation and inflammation-associated proteins were elevated in the plasma samples of patients with long COVID as compared to those without long COVID.


The results showed that compared to COVID-19 patients who had fully recovered, long COVID patients showed evidence of immune dysregulation and systemic inflammation, with the distribution of T cells exhibiting global differences indicative of continued immune responses. The cytolytic subsets also showed sex-specific signals.

Individuals with long COVID had a significantly lower frequency of anti-SARS-CoV-2 CD8+ or cytotoxic T cells, mis-coordinated B and T-cell responses against SARS-CoV-2, elevated antibodies against SARS-CoV-2, and a higher frequency of CD4+ or helper T cells ready to migrate towards inflamed tissue.

Sex-specific differences were also observed where female patients with long COVID had lower frequencies of naive helper and cytotoxic T cells and higher levels of terminally differentiated effector memory helper and cytotoxic T cell expressing cytolytic markers and homing receptors for inflammatory tissue.

The ‘omics’ approach used in the study cumulatively indicated that individuals with long COVID showed significant gene expression changes in not only the CD4+ and CD8+ T cells but also in B cells and monocytes, with phenotypic perturbations in the helper and cytotoxic T cells overall and in those specifically against SARS-CoV-2.


Overall, the findings highlighted that patients with long COVID exhibit significant immune-associated changes and phenotypic alterations in T cells and other immune cells that could be the mechanistic basis for the persistent and wide-ranging symptoms associated with long COVID. A miscommunication or error in crosstalk between humoral and cellular adaptive immunity involving B and T cells could contribute to inflammation, immune dysregulation, and the clinical symptoms characteristic of long COVID.

Journal reference:
  • Yin, K., Peluso, M. J., Luo, X., Thomas, R., Shin, M., Neidleman, J., Andrew, A., Young, K. C., Ma, T., Hoh, R., Anglin, K., Huang, B., Argueta, U., Lopez, M., Valdivieso, D., Asare, K., Deveau, T., Munter, S. E., Ibrahim, R., & Ständker, L. (2024). Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARSCoV2. Nature Immunology., 
Dr. Chinta Sidharthan

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.


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