Expression of Foxp3 by T follicular helper cells in end-stage germinal centers

Jacobsen, Johanne T.; Hu, Wei; Castro, Tiago B. R.; Solem, Sigrid; Galante, Alice; Lin, Zeran; Allon, Samuel J.; Mesin, Luka; Bilate, Angelina M.; Schiepers, Arïen; Shalek, Alex K.; Rudensky, Alexander Y.; Victora, Gabriel D.

doi:10.1126/science.abe5146

Cited by 80 publications

(84 citation statements)

References 65 publications

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“…This suggests that Foxp3 - cells acquired Foxp3 expression after tamoxifen has been cleared, thus giving rise to a Tfr-like population that has escaped ICOS ablation. These findings fit with a recent report showing that Tfh cells can acquire Foxp3 expression at the end-stage of GC reactions 24 . We will henceforth use the term “Tfh-like Tfr” to refer to this population.…”

Section: Resultssupporting

confidence: 93%

“…The fact that a portion of mature Tfh cells can acquire Foxp3 expression has been recently confirmed by Jacobsen et al . 24 . However, the authors observed this population arising in end-stage germinal centers up to 20 days post-immunization.…”

Section: Discussionmentioning

confidence: 99%

“…Strong IL-2 signaling was shown to inhibit Tfr differentiation which is more akin to Tfh cells rather than Tregs 22 . Interestingly, recent reports provide evidence that Tfh cells can also give rise to Tfr-like cells 23,24 . While the in vivo role of Tfr cells has been controversial, they display suppressive abilities on T cell proliferation, antibody secretion and cytokine production in vitro 25,26 .…”

Section: Introductionmentioning

confidence: 99%

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ICOS costimulation is indispensable for the differentiation of T follicular regulatory cells

Panneton

Mindt

Bouklouch

et al. 2021

Preprint

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The inducible costimulator (ICOS) is a T cell costimulatory receptor critical for humoral immunity. In mice and humans, ICOS deficiency leads to a lack of T follicular helper (Tfh) cells and protective antibodies. However, the role of ICOS in T follicular regulatory (Tfr) cell generation and function remains poorly understood. Using Foxp3-cre-mediated ICOS knockout (ICOS FC) mice, we show that T regulatory (Treg)-specific ICOS deletion drastically reduces the number of Tfr cells without altering Treg cell numbers. Further, we observed a lowered ratio of antigen-specific germinal center B (GC B) cells and increased anti-nuclear antibodies in ICOS FC mice, suggesting a rise of autoreactive GC B cells. Single-cell transcriptome analysis revealed shifts in transitory Tfr precursor populations in immunized ICOS FC mice. Mechanistically, our data suggest that ICOS promotes the Treg-to-Tfr transition by regulating KLF2 and NFAT2 with downstream impacts on Bcl6 and CXCR5 expression. Importantly, we discovered a Tfr subset originating from Foxp3- precursors by analyzing flow cytometry data of immunized mice in which ICOS expression in Foxp3+ cells was ablated at different stages of GC reactions. Consistently, single-cell transcriptome analysis of global follicular T cells revealed a subset of Tfh-like cells beginning to express Foxp3 at day 6 post-immunization. These Tfh-like Tfr cells appear to promote GC B cell expansion and plasma cell differentiation in an ICOS-dependent manner. Taken together, we propose that Tfr cells derived from natural Tregs suppress the expansion of autoreactive GC B cells whereas Tfh-like Tfr cells promote early-stage GC output. Further, these Tfr subsets depend on ICOS costimulation for their differentiation or function.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ICOS costimulation is indispensable for the differentiation of T follicular regulatory cells

Panneton

Mindt

Bouklouch

et al. 2021

Preprint

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“…We note that the trends were not a consequence of the GC collapse brought about by decaying antigen levels. The trends remained even without GC collapse or when the collapse was due to alternative mechanisms such as restricted T fh cell help ( 57 ) ( Supplementary Figure 9 ). That GCs following COVID-19 vaccination can persist over extended durations ( 24 , 58 ) suggests that GC shrinkage may be slow in vivo .…”

Section: Resultsmentioning

confidence: 97%

Increased B Cell Selection Stringency In Germinal Centers Can Explain Improved COVID-19 Vaccine Efficacies With Low Dose Prime or Delayed Boost

et al. 2021

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The efficacy of COVID-19 vaccines appears to depend in complex ways on the vaccine dosage and the interval between the prime and boost doses. Unexpectedly, lower dose prime and longer prime-boost intervals have yielded higher efficacies in clinical trials. To elucidate the origins of these effects, we developed a stochastic simulation model of the germinal center (GC) reaction and predicted the antibody responses elicited by different vaccination protocols. The simulations predicted that a lower dose prime could increase the selection stringency in GCs due to reduced antigen availability, resulting in the selection of GC B cells with higher affinities for the target antigen. The boost could relax this selection stringency and allow the expansion of the higher affinity GC B cells selected, improving the overall response. With a longer dosing interval, the decay in the antigen with time following the prime could further increase the selection stringency, amplifying this effect. The effect remained in our simulations even when new GCs following the boost had to be seeded by memory B cells formed following the prime. These predictions offer a plausible explanation of the observed paradoxical effects of dosage and dosing interval on vaccine efficacy. Tuning the selection stringency in the GCs using prime-boost dosages and dosing intervals as handles may help improve vaccine efficacies.

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“…In contrast, suppressive CD4 + FOXP3+ T regulatory (T reg ) cells, called T follicular regulatory (T FR ) cells, limit the function and output of GC reaction ( Chung et al, 2011 ; Wollenberg et al, 2011 ). While T FR cells dominate the early-GC ( Wing et al, 2017 ), a distinct T reg population prevails in the late-GC ( Jacobsen et al, 2021 ). These recently described cells seem to arise from T FH cells, however it remains unclear what triggers their acquisition of regulatory properties ( Jacobsen et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Immune Epigenetic Crosstalk Between Malignant B Cells and the Tumor Microenvironment in B Cell Lymphoma

2022

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Epigenetic reprogramming is a hallmark of lymphomagenesis, however its role in reshaping the tumor microenvironment is still not well understood. Here we review the most common chromatin modifier mutations in B cell lymphoma and their effect on B cells as well as on T cell landscape. We will also discuss precision therapy strategies to reverse their aberrant signaling by targeting mutated proteins or counterbalance epigenetic mechanisms.

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Expression of Foxp3 by T follicular helper cells in end-stage germinal centers

Cited by 80 publications

References 65 publications

ICOS costimulation is indispensable for the differentiation of T follicular regulatory cells

ICOS costimulation is indispensable for the differentiation of T follicular regulatory cells

Increased B Cell Selection Stringency In Germinal Centers Can Explain Improved COVID-19 Vaccine Efficacies With Low Dose Prime or Delayed Boost

Immune Epigenetic Crosstalk Between Malignant B Cells and the Tumor Microenvironment in B Cell Lymphoma

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