Silvia Innocentin, Ross McKenzie, Jayalini Assalaarachchi, Helena A Carslaw, Anusha Gupta, Sanne Cole, Adrian Liston, Michelle A Linterman, Louise Webb, Alice R Burton
{"title":"IL-2 silencing enables Tfh cell expansion during vaccination but is redundant for antibody production","authors":"Silvia Innocentin, Ross McKenzie, Jayalini Assalaarachchi, Helena A Carslaw, Anusha Gupta, Sanne Cole, Adrian Liston, Michelle A Linterman, Louise Webb, Alice R Burton","doi":"10.1111/imcb.70084","DOIUrl":"10.1111/imcb.70084","url":null,"abstract":"<p>Vaccines stimulate protective humoral immunity by coordinating lymphocyte activity in the germinal center (GC) response. However, the degree of protection varies across the population, with older individuals often showing lower titer antibody responses to vaccines. Previous work has correlated increased exposure to Th1 cytokines, like IL-2, with poor antibody responses in aging. Whether this is a causal relationship is unknown. Here we used <i>Il2</i><sup>cre/+</sup>; <i>Rosa26</i><sup>stop-flox-Il2/+</sup> mice, which cannot shut down IL-2 production once initiated, to test the hypothesis that sustained IL-2 exposure affects the GC response and antibody production post vaccination. Prolonged IL-2 production impeded T follicular helper (Tfh) cell differentiation, with reduced numbers of GC Tfh, pre-Tfh and T follicular regulatory cells consistently observed in the draining lymph node of <i>Il2</i><sup>cre/+</sup>; <i>Rosa26</i><sup>stop-flox-Il2/+</sup> mice at day 10 post immunization, relative to control mice. Numbers of Tfh cells remained suppressed at day 21 post immunization and corresponded with reduced GC B cell formation, including NP-specific IgG1<sup>+</sup> class-switched GC B cells. As a core output of the GC response, B220<sup>−</sup>IRF4<sup>+</sup>CD138<sup>+</sup> antibody-secreting cells (ASCs) were significantly reduced in the bone marrow of <i>Il2</i><sup>cre/+</sup>; <i>Rosa26</i><sup>stop-flox-Il2/+</sup> mice, 10 days post NP-KLH immunization compared to control mice. However, by day 21, antigen-specific humoral immunity was restored, with similar levels of B220<sup>−</sup>IRF4<sup>+</sup>CD138<sup>+</sup> and NP-specific ASCs in both experimental and control groups. In summary, while sustained IL-2 production delayed Tfh differentiation and early GC formation, it did not affect overall antibody titers after vaccination.</p>","PeriodicalId":179,"journal":{"name":"Immunology & Cell Biology","volume":"104 4","pages":"316-328"},"PeriodicalIF":3.0,"publicationDate":"2026-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imcb.70084","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147275318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Samuel WJ Smith-Bell, Joshua C Halpin, Phillip K Darcy, Thiloma Liyanage, Lachlan J Dobson, Alexander D McLellan
{"title":"Auto-inducible expression of chimeric antigen receptor T cells using the NR4A1 promoter","authors":"Samuel WJ Smith-Bell, Joshua C Halpin, Phillip K Darcy, Thiloma Liyanage, Lachlan J Dobson, Alexander D McLellan","doi":"10.1111/imcb.70095","DOIUrl":"10.1111/imcb.70095","url":null,"abstract":"<p>Chimeric antigen receptor (CAR) T cell therapies have shown remarkable efficacy in hematological malignancies, yet translation to solid tumors has been hindered by immunosuppressive tumor microenvironments, reduced T cell persistence and on-target/off-tumor toxicities. Constitutive CAR expression, typically driven by strong promoters such as EF1α, promotes tonic signaling, receptor clustering and antigen-independent activation, contributing to T cell exhaustion and adverse events. Inducible promoter systems have been proposed to improve control over CAR expression. NR4A1, a transcription factor (TF) activated during early T cell receptor (TCR) signaling, governs pathways central to T cell activation and dysfunction, making its promoter an attractive candidate for conditional CAR regulation. We compared constitutive (EF1α), synthetic inducible (6NFAT-NFκB and 2NFAT-2NurRE) and NR4A1 promoters to drive expression of a second-generation FRP5-CAR. NR4A1-driven CARs demonstrated low basal expression that was rapidly induced upon antigen encounter, reaching levels equivalent to EF1α-driven CARs while showing minimal antigen-independent signaling. Functionally, NR4A1-driven CARs mediated potent tumor lysis, preserved a less exhausted (PD-1<sup>low</sup> and TIM-3<sup>low</sup>) and more memory-like phenotype (CD62L<sup>high</sup> and CD45RA<sup>high</sup>), and sustained robust antitumor responses in vitro and in vivo. These findings establish the NR4A1 promoter as a native, activation-inducible system to fine-tune CAR expression, while maintaining therapeutic efficacy comparable to constitutively expressed CAR T cells. This strategy provides a promising framework for advancing CAR T cell therapies against solid tumors.</p>","PeriodicalId":179,"journal":{"name":"Immunology & Cell Biology","volume":"104 4","pages":"381-395"},"PeriodicalIF":3.0,"publicationDate":"2026-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imcb.70095","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147375477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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