Evolution of antigen-specific follicular helper T cell transcriptional programs across effector function and through to memory

Abstract

Understanding how follicular helper T cells (TFH) regulate the specialization, maturation, and differentiation of adaptive B cell immunity is crucial for developing durable high-affinity immune protection. Using indexed-single cell molecular strategies, we reveal a skewed intra-clonal assortment of higher affinity TCR and the distinct molecular programming of the localized TFH compartment compared to emigrant conventional effector TH (ETH) cells. We find a temporal shift in BCR class switch which permits identification of inflammatory and anti-inflammatory modules of transcriptional programming that subspecialize TFH function before and during the germinal center (GC) reaction. Late collapse of this local primary GC reaction reveals a persistent post-GC TFH population which discloses a putative memory TFH program. These studies define specialized antigen-specific TFH transcriptional programs that progressively direct class-specific evolution of high-affinity B cell immunity and uncover the transcriptional program of a memory TFH population as the regulators of antigen recall. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/460841v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@17413c2org.highwire.dtl.DTLVardef@1bd505borg.highwire.dtl.DTLVardef@1e6bc99org.highwire.dtl.DTLVardef@167e6e9_HPS_FORMAT_FIGEXP M_FIG C_FIG SummaryDistinct inflammatory and anti-inflammatory antigen-specific TFH transcriptional programs regulate class-specific B cell maturation. Highlights- Skewed intra-clonal assortment of high affinity TCR into the TFH compartment - Significant temporal delay in anti-inflammatory IgG1 production - Inflammatory and anti-inflammatory transcriptional modules subspecialize TFH - Late GC collapse reveals a persisting post-GC putative memory TFH compartment