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1.
Clin Immunol ; 237: 108991, 2022 04.
Article in English | MEDLINE | ID: covidwho-1866980

ABSTRACT

Many studies have been performed in severe COVID-19 on immune cells in the circulation and on cells obtained by bronchoalveolar lavage. Most studies have tended to provide relative information rather than a quantitative view, and it is a combination of approaches by various groups that is helping the field build a picture of the mechanisms that drive severe lung disease. Approaches employed to date have not revealed information on lung parenchymal T cell subsets in severe COVID-19. Therefore, we sought to examine early and late T cell subset alterations in the lungs and draining lymph nodes in severe COVID-19 using a rapid autopsy protocol and quantitative imaging approaches. Here, we have established that cytotoxic CD4+ T cells (CD4 + CTLs) increase in the lungs, draining lymph nodes and blood as COVID-19 progresses. CD4 + CTLs are prominently expanded in the lung parenchyma in severe COVID-19. In contrast CD8+ T cells are not prominent, exhibit increased PD-1 expression, and no obvious increase is seen in the number of Granzyme B+ CD8+ T cells in the lung parenchyma in severe COVID-19. Based on quantitative evidence for re-activation in the lung milieu, CD4 + CTLs may be as likely to drive viral clearance as CD8+ T cells and may also be contributors to lung inflammation and eventually to fibrosis in severe COVID-19.


Subject(s)
CD4-Positive T-Lymphocytes , COVID-19 , CD8-Positive T-Lymphocytes , Humans , Lung , T-Lymphocyte Subsets , T-Lymphocytes, Cytotoxic
2.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-313719

ABSTRACT

The SARS-CoV-2 genome encodes many proteins that directly compromise Type I interferon-mediated innate immunity. In acute COVID-19 the consequent dysregulated hyper-inflammatory state alters the milieu of draining lymph nodes and indirectly induces anatomically restricted, weeks-long transient defects in adaptive immunity. The striking attenuation of discrete aspects of T cell immunity may facilitate the evolution of more transmissible viral variants. No techniques employed to date, including single nuclear sequencing, have revealed information on pulmonary T cell subsets in severe COVID-19. Here we demonstrate an unexpected paucity of total CD8+T cells and CD8+Granzyme B+ T cells in the lung parenchyma in acute COVID-19. Apart from broadly compromising the generation of T FH cells in draining lymph nodes, acute COVID-19 is also linked to attenuated CD8+ T cell activation and infiltration of the lungs, and the delayed pulmonary accumulation of CD4+T cells with a cytotoxic phenotype.Funding Information: This work was supported by NIH U19 AI110495 to SP. Funding for these studies from the Massachusetts Consortium of Pathogen Readiness, the Mark and Lisa Schwartz Foundation and Enid Schwartz is also acknowledged.Declaration of Interests: SP is on the Scientific Advisory Board of Abpro Inc and BeBio. Thereare no other competing interests for any of the authors.Ethics Approval Statement: This study was conducted with the approval of the Institutional Review Boards at the Massachusetts General Hospital and the Brigham and Women’s Hospital.

3.
PubMed; 2020.
Preprint in English | PubMed | ID: ppcovidwho-292772

ABSTRACT

Humoral responses in COVID-19 disease are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined postmortem thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers, a striking reduction in Bcl-6+ germinal center B cells but preservation of AID+ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6+TFH cell differentiation together with an increase in T-bet+TH1 cells and aberrant extra-follicular TNF-a accumulation. Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific "disease-related" B cell populations. These data identify defective Bcl-6+TFH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections and suggest that achieving herd immunity through natural infection may be difficult. Funding: This work was supported by NIH U19 AI110495 to SP, NIH R01 AI146779 to AGS, NIH R01AI137057 and DP2DA042422 to DL, BMH was supported by NIGMS T32 GM007753, TMC was supported by T32 AI007245. Funding for these studies from the Massachusetts Consortium of Pathogen Readiness, the Mark and Lisa Schwartz Foundation and Enid Schwartz is also acknowledged. Conflict of Interest: None. Ethical Approval: This study was performed with the approval of the Institutional Review Boards at the Massachusetts General Hospital and the Brigham and Women's Hospital.

6.
Cell ; 183(1): 143-157.e13, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-720447

ABSTRACT

Humoral responses in coronavirus disease 2019 (COVID-19) are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined post mortem thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers and a striking reduction in Bcl-6+ germinal center B cells but preservation of AID+ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6+ TFH cell differentiation together with an increase in T-bet+ TH1 cells and aberrant extra-follicular TNF-α accumulation. Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific "disease-related" B cell populations. These data identify defective Bcl-6+ TFH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections, and suggest that achieving herd immunity through natural infection may be difficult.


Subject(s)
Coronavirus Infections/immunology , Germinal Center/immunology , Pneumonia, Viral/immunology , T-Lymphocytes, Helper-Inducer/immunology , Aged , Aged, 80 and over , B-Lymphocytes/immunology , COVID-19 , Female , Germinal Center/pathology , Humans , Male , Middle Aged , Pandemics , Proto-Oncogene Proteins c-bcl-6/genetics , Proto-Oncogene Proteins c-bcl-6/metabolism , Spleen/immunology , Spleen/pathology , Tumor Necrosis Factor-alpha/metabolism
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