IL-21R signal reprogramming cooperates with CD40 and BCR signals to select and differentiate germinal center B cells

Luo, Wei; Conter, Laura; Elsner, Rebecca A.; Smita, Shuchi; Weisel, Florian; Callahan, Derrick; Wu, Shengji; Chikina, Maria; Shlomchik, Mark J.

doi:10.1126/sciimmunol.add1823

Cited by 35 publications

(29 citation statements)

References 70 publications

(144 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data indicate that, in addition to BCR/CD40 signaling, IL-21 signaling profoundly induces the activation of mTORC1 and c-Myc pathways. This is consistent with a recent report showing that IL-21R signaling is reprogrammed in B GC cells and, compared with BCR/CD40 combination signals, IL-21R signals in synergy with CD40 signals induce distinct differentiation characteristics in B GC cells ( 63 ). Recent reports also showed that IL-21 supports the formation of GCs at an early stage by promoting B GC cell proliferation ( 64 , 65 ) and ASC differentiation even in the absence of cognate help ( 66 ).…”

Section: Discussionsupporting

confidence: 93%

Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation

et al. 2023

View full text Add to dashboard Cite

In antibody responses, mutated germinal center B (B GC ) cells are positively selected for reentry or differentiation. As the products from GCs, memory B cells and antibody-secreting cells (ASCs) support high-affinity and long-lasting immunity. Positive selection of B GC cells is controlled by signals received through the B cell receptor (BCR) and follicular helper T (T FH ) cell–derived signals, in particular costimulation through CD40. Here, we demonstrate that the T FH cell effector cytokine interleukin-21 (IL-21) joins BCR and CD40 in supporting B GC selection and reveal that strong IL-21 signaling prioritizes ASC differentiation in vivo. B GC cells, compared with non-B GC cells, show significantly reduced IL-21 binding and attenuated signaling, which is mediated by low cellular heparan sulfate (HS) sulfation. Mechanistically, N-deacetylase and N-sulfotransferase 1 (Ndst1)–mediated N-sulfation of HS in B cells promotes IL-21 binding and signal strength. Ndst1 is down-regulated in B GC cells and up-regulated in ASC precursors, suggesting selective desensitization to IL-21 in B GC cells. Thus, specialized biochemical regulation of IL-21 bioavailability and signal strength sets a balance between the stringency and efficiency of GC selection.

show abstract

Section: Discussionsupporting

confidence: 93%

Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation

et al. 2023

View full text Add to dashboard Cite

show abstract

“…1, G and H). Previous studies demonstrated that interleukin-21 (IL-21) can increase Myc expression in vitro, suggesting a synergistic effect in selection program induction between contact-derived and paracrine signaling ( 38 , 39 ). We were able to repeat these data in vitro, yet injection of recombinant IL-21 into mice did not yield a similar outcome at the protein and RNA level in our experimental settings (fig.…”

Section: Resultsmentioning

confidence: 99%

T cell help induces Myc transcriptional bursts in germinal center B cells during positive selection

Kagan Ben Tikva,

Gurwitz,

Sivan

et al. 2024

Sci. Immunol.

View full text Add to dashboard Cite

Antibody affinity maturation occurs in secondary lymphoid organs within germinal centers (GCs). At these sites, B cells mutate their antibody-encoding genes in the dark zone, followed by preferential selection of the high-affinity variants in the light zone by T cells. The strength of the T cell–derived selection signals is proportional to the B cell receptor affinity and to the magnitude of subsequent Myc expression. However, because the lifetime of Myc mRNA and its corresponding protein is very short, it remains unclear how T cells induce sustained Myc levels in positively selected B cells. Here, by direct visualization of mRNA and active transcription sites in situ, we found that an increase in transcriptional bursts promotes Myc expression during B cell positive selection in GCs. Elevated T cell help signals predominantly enhance the percentage of cells expressing Myc in GCs as opposed to augmenting the quantity of Myc transcripts per individual cell. Visualization of transcription start sites in situ revealed that T cell help promotes an increase in the frequency of transcriptional bursts at the Myc locus in GC B cells located primarily in the LZ apical rim. Thus, the rise in Myc , which governs positive selection of B cells in GCs, reflects an integration of transcriptional activity over time rather than an accumulation of transcripts at a specific time point.

show abstract

“…Our data suggested that IL-4 signaling may differentially impact B cells at different stages of differentiation during an immune response. To test this hypothesis directly, we isolated naive splenic B cells from naive mice or GL7 + splenic B cells from mice at least 12 days post- Plasmodium infection and cultured them with an agonistic anti-CD40 antibody (1 ug/mL) to promote in vitro GC B cell survival 37,38 . Both cell types were cultured in the presence or absence of non-complexed recombinant IL-4 (10 ng/mL) for 24 hours.…”

Section: Resultsmentioning

confidence: 99%

IL-4 downregulates BCL6 to promote memory B cell selection in germinal centers

Shehata

Thouvenel

Hondowicz

et al. 2023

Preprint

View full text Add to dashboard Cite

Germinal center (GC)-derived memory B cells (MBCs) are critical for humoral immunity as they differentiate into protective antibody-secreting cells during re-infection. GC formation and cellular interactions within the GC have been studied in detail, yet the exact signals that allow for the selection and exit of MBCs are not understood. We show that IL-4 can trigger GC B cell selection and exit by inducing the negative autoregulation of BCL6, the primary GC transcription factor. High affinity/avidity GC B cells that secure additional help and upregulate MBC survival signals to replace the loss of BCL6 exit the GC as memory cells, whereas those that do not are primed for cell death. In this way, IL-4 signaling regulates selection and affinity maturation within the MBC pool.

show abstract

IL-21R signal reprogramming cooperates with CD40 and BCR signals to select and differentiate germinal center B cells

Cited by 35 publications

References 70 publications

Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation

Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation

T cell help induces Myc transcriptional bursts in germinal center B cells during positive selection

IL-4 downregulates BCL6 to promote memory B cell selection in germinal centers

Contact Info

Product

Resources

About