IL-4 Signaling Regulates the Fate of B Cell Differentiation and limits BCR repertoire

Abstract

Abstract Il-4 has a critical role in organizing the peripheral lymph nodes in homeostasis and after vaccination. To further understand the molecular mechanisms and their impact in the immune response, we used single cell RNA-Seq of CD45+ cells in 4get and 4getIL4R−/− mice following tetanus/diphtheria immunization. We found that the lack of IL-4 signaling restrains the expression of key co-stimulatory and differentiation molecules CD83, CD86, and xbp1, while upregulating the jun/junb/fos pathways. These alterations result in reduced B cell proliferation and differentiation into plasma cells. Surprisingly, we found that in the absence of IL-4 signaling the ratio of dark to light zone residing germinal center shifts from the normal ratio to one dominated by the dark zone. The increase in Dark Zone germinal centers lead to an increase in the diversity of the repertoire in vaccinated 4getIL4R−/− mice as confirmed by VDJ-seq. We also observed that the upregulation of the transcription factor T-bet has the capacity of inducing a similar phenotype. Finally, even though the amount of memory B cells was increased in the absence of IL-4 signaling, we observed that these cells are not able to respond to a secondary challenge. These data suggest a pivotal role for IL-4 in governing B-cell differentiation and the development of optimal cellular and humoral immunity to vaccination. supported by grants from NIH R01 AI135045