GM-CSF-activated human dendritic cells promote type1 T follicular helper cells (Tfh1) polarization in a CD40-dependent manner

  1. Sarantis Korniotis
  2. Melissa Saichi
  3. Coline Trichot
  4. Caroline Hoffmann
  5. Elise Amblard
  6. Annick Viguier
  7. Sophie Grondin
  8. Floriane Noel
  9. Hamid Mattoo
  10. Vassili Soumelis

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Abstract

T follicular helper (Tfh) cells are specialized CD4 + T cells that regulate humoral immunity by providing B cell help. Tfh1 sub-population was recently identified and associated with severity in infection and autoimmune diseases. The cellular and molecular requirements to induce human Tfh1 differentiation are unknown. Our work investigated the role of human dendritic cells (DC) in promoting Tfh1 differentiation and their physiopathological implication in mycobacterium tuberculosis and mild COVID-19 infection.

Activated human blood CD1c + DC were cocultured with allogeneic naive CD4 + T cells. Single-cell RNA sequencing was then used alongside protein validation to define the induced Tfh lineage. DC signature and correlation with Tfh1 cells in infected patients was established through bioinformatic analysis.

Our results show that GM-CSF-activated DC drove the differentiation of Tfh1 cells, displaying typical Tfh molecular features, including 1) high levels of PD-1, CXCR5, and ICOS expression; 2) BCL6 and TBET co-expression; 3) IL-21 and IFN-γ secretion. Mechanistically, GM-CSF triggered the emergence of two distinct DC sub-populations defined by their differential expression of CD40 and ICOS-ligand (ICOS-L), and distinct phenotype, morphology, transcriptomic signature, and function. We showed that Tfh1 differentiation was efficiently and specifically induced by CD40 high ICOS-L low DC in a CD40-dependent manner. Tfh1 cells were positively associated with a CD40 high ICOS-L Low DC signature in patients with latent mycobacterium tuberculosis and mild COVID-19 infection.

Our study uncovers a novel CD40-dependent human Tfh1 axis. Immunotherapy modulation of Tfh1 activity might contribute to control diseases where Tfh1 are known to play a key role, such as infections.

Significance Statement

Dendritic cells (DC) play a central role in triggering the adaptive immune response due to their T cell priming functions. Among different T cell subsets, it is still not clear how human type1 T follicular helper cells (Tfh1) differentiate. Tfh1 cells are implicated in several physiopathological conditions, including infections. Here we show that GM-CSF induces diversification of human DC. Only CD40 high ICOS-L Low DC were able to drive Tfh1 cell differentiation. We found that CD40 high ICOS-L Low DC signature was associated to Tfh1 cells in mycobacterium tuberculosis and COVID-19 patients. Our data reveal a previously undescribed pathway leading to human Tfh1 cell differentiation and highlight the importance of GM-CSF and CD40 as potential targets for the design of anti-infective therapies.

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  1. ScreenIT

    SciScore for 10.1101/2022.04.28.489850: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Antibodies
    SentencesResources
    Blocking Experiments: DC were incubated at 37°C with 50 ng/ml anti–human CD40 antibody, or 50ng/ml anti-human ICOS-L or 50ng/ml of the corresponding isotype control (Biolegend).
    CD40 antibody
    suggested: None
    anti-human ICOS-L
    suggested: (Thermo Fisher Scientific Cat# 14-5889-80, RRID:AB_467683)
    Software and Algorithms
    SentencesResources
    Library quality and quantity were analyzed by Agilent Bioanalyzer 2100 and Life Technologies Qubit 3.0 Fluorometer.
    Agilent Bioanalyzer
    suggested: None
    The reads were first mapped to the hg19 UCSC transcript set using Bowtie2 version 2.1.0 and the gene expression level was estimated using RSEM v1.2.15.
    Bowtie2
    suggested: (Bowtie 2, RRID:SCR_016368)
    RSEM
    suggested: (RSEM, RRID:SCR_013027)
    Downstream analyses were performed using R (v3.6.0) and DESeq2 package (v1.26.0)
    DESeq2
    suggested: (DESeq, RRID:SCR_000154)
    Differentially expressed genes were determined with an absolute log-fold change threshold at 2 and an adjusted p-value below 0.01 Microarray Data analysis: We loaded the normalized dataset using GEOquery R package, and GSE19904 as studyID.
    GEOquery
    suggested: (GEOquery, RRID:SCR_000146)

    Results from OddPub: Thank you for sharing your code.

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  2. Version published to 10.1101/2022.04.28.489850v1 on bioRxiv