The Journal of Experimental Medicine

Brabec, Tomáš;Schwarzer, Martin;Kováčová, Katarína;Dobešová, Martina;Schierová, Dagmar;Březina, Jiří;Pacáková, Iva;Šrůtková, Dagmar;Ben-Nun, Osher;Goldfarb, Yael;Šplíchalová, Iva;Kolář, Michal;Abramson, Jakub;Filipp, Dominik;Dobeš, Jan

doi: 10.1084/jem.2023019411132023cpmid: 37987749

De Martin, Angelina;Stanossek, Yves;Pikor, Natalia Barbara;Ludewig, Burkhard

doi: 10.1084/jem.20221220pmid: 38038708

Fibroblastic reticular cells (FRCs) are specialized fibroblasts of secondary lymphoid organs that provide the structural foundation of the tissue. Moreover, FRCs guide immune cells to dedicated microenvironmental niches where they provide lymphocytes and myeloid cells with homeostatic growth and differentiation factors. Inflammatory processes, including infection with pathogens, induce rapid morphological and functional adaptations that are critical for the priming and regulation of protective immune responses. However, adverse FRC reprogramming can promote immunopathological tissue damage during infection and autoimmune conditions and subvert antitumor immune responses. Here, we review recent findings on molecular pathways that regulate FRC–immune cell crosstalk in specialized niches during the generation of protective immune responses in the course of pathogen encounters. In addition, we discuss how FRCs integrate immune cell–derived signals to ensure protective immunity during infection and how therapies for inflammatory diseases and cancer can be developed through improved understanding of FRC–immune cell interactions.

Fregona, Vincent;Bayet, Manon;Bouttier, Mathieu;Largeaud, Laetitia;Hamelle, Camille;Jamrog, Laura A.;Prade, Naïs;Lagarde, Stéphanie;Hebrard, Sylvie;Luquet, Isabelle;Mansat-De Mas, Véronique;Nolla, Marie;Pasquet, Marlène;Didier, Christine;Khamlichi, Ahmed Amine;Broccardo, Cyril;Delabesse, Éric;Mancini, Stéphane J.C.;Gerby, Bastien

doi: 10.1084/jem.20230279pmid: 37930337

B cell acute lymphoblastic leukemia (B-ALL) is a multistep disease characterized by the hierarchical acquisition of genetic alterations. However, the question of how a primary oncogene reprograms stem cell–like properties in committed B cells and leads to a preneoplastic population remains unclear. Here, we used the PAX5::ELN oncogenic model to demonstrate a causal link between the differentiation blockade, the self-renewal, and the emergence of preleukemic stem cells (pre-LSCs). We show that PAX5::ELN disrupts the differentiation of preleukemic cells by enforcing the IL7r/JAK-STAT pathway. This disruption is associated with the induction of rare and quiescent pre-LSCs that sustain the leukemia-initiating activity, as assessed using the H2B-GFP model. Integration of transcriptomic and chromatin accessibility data reveals that those quiescent pre-LSCs lose B cell identity and reactivate an immature molecular program, reminiscent of human B-ALL chemo-resistant cells. Finally, our transcriptional regulatory network reveals the transcription factor EGR1 as a strong candidate to control quiescence/resistance of PAX5::ELN pre-LSCs as well as of blasts from human B-ALL.

Brabec, Tomáš;Schwarzer, Martin;Kováčová, Katarína;Dobešová, Martina;Schierová, Dagmar;Březina, Jiří;Pacáková, Iva;Šrůtková, Dagmar;Ben-Nun, Osher;Goldfarb, Yael;Šplíchalová, Iva;Kolář, Michal;Abramson, Jakub;Filipp, Dominik;Dobeš, Jan

doi: 10.1084/jem.20230194pmid: 37902602

Intestinal epithelial cells have the capacity to upregulate MHCII molecules in response to certain epithelial-adhesive microbes, such as segmented filamentous bacteria (SFB). However, the mechanism regulating MHCII expression as well as the impact of epithelial MHCII–mediated antigen presentation on T cell responses targeting those microbes remains elusive. Here, we identify the cellular network that regulates MHCII expression on the intestinal epithelium in response to SFB. Since MHCII on the intestinal epithelium is dispensable for SFB-induced Th17 response, we explored other CD4+ T cell–based responses induced by SFB. We found that SFB drive the conversion of cognate CD4+ T cells to granzyme+ CD8α+ intraepithelial lymphocytes. These cells accumulate in small intestinal intraepithelial space in response to SFB. Yet, their accumulation is abrogated by the ablation of MHCII on the intestinal epithelium. Finally, we show that this mechanism is indispensable for the SFB-driven increase in the turnover of epithelial cells in the ileum. This study identifies a previously uncharacterized immune response to SFB, which is dependent on the epithelial MHCII function.

ElTanbouly, Mohamed A.;Ramos, Victor;MacLean, Andrew J.;Chen, Spencer T.;Loewe, Maximilian;Steinbach, Sandra;Ben Tanfous, Tarek;Johnson, Brianna;Cipolla, Melissa;Gazumyan, Anna;Oliveira, Thiago Y.;Nussenzweig, Michel C.

doi: 10.1084/jem.20231838pmid: 37938344

Protective immune responses to many pathogens depend on the development of high-affinity antibody-producing plasma cells (PC) in germinal centers (GCs). Transgenic models suggest that there is a stringent affinity-based barrier to PC development. Whether a similar high-affinity barrier regulates PC development under physiologic circumstances and the nature of the PC fate decision has not been defined precisely. Here, we use a fate-mapping approach to examine the relationship between GC B cells selected to undergo additional rounds of affinity maturation, GC pre-PC, and PC. The data show that initial PC selection overlaps with GC B cell selection, but that the PC compartment accumulates a less diverse and higher affinity collection of antibodies over time. Thus, whereas the GC continues to diversify over time, affinity-based pre-PC selection sieves the GC to enable the accumulation of a more restricted group of high-affinity antibody-secreting PC.

Yang, Yi;Cadwell, Ken

doi: 10.1084/jem.20232011pmid: 38091026

Type I interferons are best known for their antiviral role. Here, Ayala et al. (https://doi.org/10.1084/jem.20230063) reveal that commensal bacteria elicit tonic type I interferons to prime dendritic cells and induce regulatory T cells that maintain a tolerogenic intestinal milieu.

Fu, Jianing;Wang, Zicheng;Martinez, Mercedes;Obradovic, Aleksandar;Jiao, Wenyu;Frangaj, Kristjana;Jones, Rebecca;Guo, Xinzheng V.;Zhang, Ya;Kuo, Wan-I;Ko, Huaibin M.;Iuga, Alina;Bay Muntnich, Constanza;Prada Rey, Adriana;Rogers, Kortney;Zuber, Julien;Ma, Wenji;Miron, Michelle;Farber, Donna L.;Weiner, Joshua;Kato, Tomoaki;Shen, Yufeng;Sykes, Megan

doi: 10.1084/jem.20230930pmid: 38091025

The site of transition between tissue-resident memory (TRM) and circulating phenotypes of T cells is unknown. We integrated clonotype, alloreactivity, and gene expression profiles of graft-repopulating recipient T cells in the intestinal mucosa at the single-cell level after human intestinal transplantation. Host-versus-graft (HvG)–reactive T cells were mainly distributed to TRM, effector T (Teff)/TRM, and T follicular helper compartments. RNA velocity analysis demonstrated a trajectory from TRM to Teff/TRM clusters in association with rejection. By integrating pre- and post-transplantation (Tx) mixed lymphocyte reaction–determined alloreactive repertoires, we observed that pre-existing HvG-reactive T cells that demonstrated tolerance in the circulation were dominated by TRM profiles in quiescent allografts. Putative de novo HvG-reactive clones showed a transcriptional profile skewed to cytotoxic effectors in rejecting grafts. Inferred protein regulon network analysis revealed upstream regulators that accounted for the effector and tolerant T cell states. We demonstrate Teff/TRM interchangeability for individual T cell clones with known (allo)recognition in the human gut, providing novel insight into TRM biology.

Yada, Yutaro;Matsumoto, Masanori;Inoue, Takeshi;Baba, Akemi;Higuchi, Ryota;Kawai, Chie;Yanagisawa, Masashi;Kitamura, Daisuke;Ohga, Shouichi;Kurosaki, Tomohiro;Baba, Yoshihiro

doi: 10.1084/jem.20222178pmid: 37902601

Positive selection of high-affinity germinal center (GC) B cells is driven by antigen internalization through their B cell receptor (BCR) and presentation to follicular helper T cells. However, the requirements of BCR signaling in GC B cells remain poorly understood. Store-operated Ca2+ entry, mediated by stromal interacting molecule 1 (STIM1) and STIM2, is the main Ca2+ influx pathway triggered by BCR engagement. Here, we showed that STIM-deficient B cells have reduced B cell competitiveness compared with wild-type B cells during GC responses. B cell–specific deletion of STIM proteins decreased the number of high-affinity B cells in the late phase of GC formation. STIM deficiency did not affect GC B cell proliferation and antigen presentation but led to the enhancement of apoptosis due to the impaired upregulation of anti-apoptotic Bcl2a1. STIM-mediated activation of NFAT was required for the expression of Bcl2a1 after BCR stimulation. These findings suggest that STIM-mediated survival signals after antigen capture regulate the optimal selection and maintenance of GC B cells.

Dominguez-Sola, David

doi: 10.1084/jem.20231821pmid: 38051276

In this issue of JEM, Yada et al. (https://doi.org/10.1084/jem.20222178) demonstrate that effective antibody affinity selection in germinal centers relies on the store-operated calcium entry (SOCE) component of the B cell receptor (BCR) signaling network. Therefore, active BCR signaling is as relevant to positive selection as the function of BCRs as endocytic receptors, answering a question that had puzzled experts for a while. These findings transform our understanding of the mechanisms supporting adaptive immune responses (to vaccines, for example) and have important implications for interpreting the genomics and pathogenesis of germinal center–derived B cell lymphomas.