The loss of Bcl-6 expressing T follicular helper cells and the absence of germinal centers in COVID-19
T cell immunology/immunity inflammation
Authors: Kaneko, N.; Kuo, H.; Boucau, J.; Farmer, J. R. et al.
Link to paper: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3652322
Journal/ Pre-Print:SSRN, In Review for Immunity
Tags: Immunology/Immunity, Inflammation, B cells, T cells (Tfh)
Splenic and lymph node B cells and T follicular helper cells show a significant reduction in Bcl-6 expression in situ.
The CD4 T cell compartment found in the lymph nodes and spleens of patients that succumbed early (up to 10 days after respiratory symptoms) or late (16-36 days after hospitalization) to COVID-19, exhibit increased frequencies of Th1-phenotype cells, which promote an inflammatory milieu (TNF-a production), potentially contributing to the loss of germinal centres in SARS-CoV-2 patients.
Inflammation correlates with increased presence of SARS-CoV-2-specific circulating plasmablasts, which are likely extrafollicularly derived.
The authors aim to tackle the question of the variable and often short-lived humoral response to SARS-CoV-2. They use multicolour imaging of post-mortem isolated thoracic lymph nodes and spleens to look at the tissue architecture and cell composition in situ. Using this approach, the authors find that germinal centres, the generation site of plasma cells producing high-affinity antibodies and long-lived memory B cells, are lost. They could correlate this striking disturbance in lymphoid architecture to significant loss of Bcl-6 expression in B cells and T follicular helper cells, the latter being absolutely essential for the germinal centre reaction, which explains their absence. In the secondary lymphoid organs of the analysed cohort, CD4+ T cell differentiation is skewed towards a Th1 phenotype concurring increased TNFa expression. Lastly, using a new (living) patient cohort, the authors corroborate some of the results by detecting an increased presence of SARS-CoV-2-specific activated B cells (including plasmablasts) in the circulation. The authors presume that these plasmablasts may be of extrafollicular origin and hence explain an impaired humoral response.
Impact for SARS-CoV2/COVID19 research efforts
Understand the immune response to SARS-CoV2/COVID19
The study took a closer look at the immune reaction in secondary lymphoid organs. Their data suggests that loss of appropriate germinal centre responses may be an explanation for low antibody protectivity and variable humoral responses in SARS-CoV-2 patients.
Clinical Cohort study
Post-Mortem Patient study
Strengths and limitations of the paper
Novelty: This study allows a possibly mechanistical human in vivo insight in the humoral response to SARS-CoV-2. It highlights that the absence of Bcl-6 expression and loss of germinal centre formation, which is accompanied by high TNF-a production in secondary lymphoid organs, may impair the humoral response to SARS-CoV-2.
Standing in the field:The importance and efficiency as well as the duration of the humoral
response to SARS-CoV2 is currently still under debate with some reports suggesting a short-lived response whereas other show sustained antibody titres.
The results are coherent with knowledge (as the authors themselves discuss) from other similar coronaviruses.
Appropriate statistics:Statistics seem appropriate.
Viral model used:Post-Mortem spleens from human patients were used for this study
who were infected with SARS-CoV-2
Translatability:Medium to High. Loss of germinal centres suggest that SARS-CoV-2 immune responses can have impinged long-term humoral immunity, which has relevance in the context of natural herd immunity and vaccination setups. Furthermore, as TNF exacerbated production correlates with impaired Tfh differentiation (due to low Bcl6 expression), which results in germinal centre loss, potentially anti-inflammatory drugs (anti-TNF) may be a translational approach to overcome these issues.
The authors do not state the age of their control group unfortunately
Enumeration of cell subsets in situ are all performed using image analysis. We acknowledge the value of spatial information, but would have been interested to know if when some of the samples would have been analysed by flow cytometry whether the data would be confirmed.
Possible out of the scope of this paper, but it would have been valuable to know what type of plasmablasts were found in the circulation (IgM vs IgG).
In addition, it would have been good to correlate plasmablast presence with neutralization assays to see whether the antibodies produced are (despite being of presumably extrafollicular origin) of good quality
The authors show TNFa expression in spleen and lymph nodes, but later only correlate their parameters to CRP levels. It would be good to see if plasmablast frequency and Tfh frequency also correlate with TNFa (or other inflammatory markers generally found in a cytokine storm syndrome patient).