TY - JOUR TI - Th2 single-cell heterogeneity and clonal distribution at distant sites in helminth-infected mice AU - Radtke, Daniel AU - Thuma, Natalie AU - Schülein, Christine AU - Kirchner, Philipp AU - Ekici, Arif B AU - Schober, Kilian AU - Voehringer, David A2 - Malissen, Bernard A2 - Soldati-Favre, Dominique A2 - King, Carolyn Genevieve A2 - Haque, Ashraful VL - 11 PY - 2022 DA - 2022/08/11 SP - e74183 C1 - eLife 2022;11:e74183 DO - 10.7554/eLife.74183 UR - https://doi.org/10.7554/eLife.74183 AB - Th2 cells provide effector functions in type 2 immune responses to helminths and allergens. Despite knowledge about molecular mechanisms of Th2 cell differentiation, there is little information on Th2 cell heterogeneity and clonal distribution between organs. To address this, we performed combined single-cell transcriptome and T-cell receptor (TCR) clonotype analysis on murine Th2 cells in mesenteric lymph nodes (MLNs) and lung after infection with Nippostrongylus brasiliensis (Nb) as a human hookworm infection model. We find organ-specific expression profiles, but also populations with conserved migration or effector/resident memory signatures that unexpectedly cluster with potentially regulatory Il10posFoxp3neg cells. A substantial MLN subpopulation with an interferon response signature suggests a role for interferon signaling in Th2 differentiation or diversification. Further RNA-inferred developmental directions indicate proliferation as a hub for differentiation decisions. Although the TCR repertoire is highly heterogeneous, we identified expanded clones and CDR3 motifs. Clonal relatedness between distant organs confirmed effective exchange of Th2 effector cells, although locally expanded clones dominated the response. We further cloned an Nb-specific TCR from an expanded clone in the lung effector cluster and describe surface markers that distinguish transcriptionally defined clusters. These results provide insights in Th2 cell subset diversity and clonal relatedness in distant organs. KW - Th2 cells KW - TCR repertoire KW - scRNAseq KW - gene expression KW - helminth infection JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -