Regulatory T (Treg) cells are vital for immune suppression. The role of the coreceptor programmed cell death 1 receptor (PD-1) in Treg cell function is controversial. Here, we demonstrate that PD-1 deficiency enhances the function of Treg cells through expression of a compensatory network of coinhibitory receptors. CD30 has a central role within this network, driving the Treg cell suppressive function within the tumor microenvironment. Mechanistically, PD-1 deficiency enhances STAT5 signaling in Treg cells, which induces CD30 expression. These data indicate a role for PD-1 as a checkpoint that negatively controls CD30 expression in Treg cells to limit their suppressive function. Understanding the functional changes that PD-1 has on Treg cells might enable combination therapies with better treatment outcomes in cancer.
© 2025. The Author(s).

Foreign and self-antigens activate CD4+ conventional and regulatory T cells (Tregs) to promote immunity and tolerance, respectively. These cell populations, which depend on interleukin-2 (IL-2), are being expanded and engineered in vitro for adoptive cell therapy (ACT) for cancer and autoimmunity. Here, we investigate the molecular pathways underlying the in vitro expansion of human CD4+ Teff and Tregs to TCR/CD28/IL-2 signaling over 12-days. Temporal integration of differential chromatin accessibility and gene expression revealed similar responses over the first 6 days. After this time, T effector (Teff) cells showed greater expansion that was associated with more robust gene activation and chromatin opening that supported increased activation of mTORC1-dependent signaling and a more energetic phenotype. Thus, Tregs are programmed temporally for more limited expansion in vitro that may benefit ACT for cancer but may be a drawback for autoimmunity. These findings may reflect a mechanism to finely tune Treg numbers to maintain homeostasis in vivo.
© 2025 The Authors.

Gram-negative bacillary bacteremia poses a significant threat, ranking among the most severe infectious diseases capable of triggering life-threatening sepsis. Despite the unambiguous involvement of neutrophils in this potentially fatal disease, there are limited data about the molecular signaling mechanisms, phenotype, and function of human neutrophils during the early phase of gram-negative bacillary bacteremia.
By using an unbiased proteomics and flow cytometry approach, we identified an antigen-presenting cell (APC)-like phenotype in human peripheral blood neutrophils (PMN) with MHC class II molecule expression in the early phase of bacteremia. Using an in-vitro model of GM-CSF-mediated induction of APC-like phenotype in PMN, we investigated downstream signaling pathways leading to MHC class II expression.
GM-CSF stimulation of neutrophils leads to the activation of three major signaling pathways, the JAK-STAT, the mitogen-activated protein kinase (MAPK), and the phosphoinositide 3-kinase (PI3K)-Akt-mTOR pathways, while MHC class II induction is mediated by a MAPK-p38-MSK1-CREB1 signaling cascade and the MHC class II transactivator CIITA in a strictly JAK1/2 kinase-dependent manner.
This study provides new insights into the signaling pathways that induce MHC class II expression in neutrophils, highlighting the potential for therapeutic targeting of JAK1/2 signaling in the treatment of gram-negative bacteremia and sepsis. Understanding these mechanisms may open up novel approaches for managing inflammatory responses during sepsis.
Copyright © 2024 Forrer, Palianina, Stühler, Kreuzaler, Roux, Li, Schmutz, Burckhardt, Franzeck, Finke, Schmidt, Bumann and Khanna.

Cytokines regulate immune responses by binding to cell surface receptors, including the common subunit beta (βc), which mediates signaling for GM-CSF, IL-3, and IL-5. Despite known roles in inflammation, the structural basis of IL-5 receptor activation remains unclear. We present the cryo-EM structure of the human IL-5 ternary receptor complex, revealing architectural principles for IL-5, GM-CSF, and IL-3. In mammalian cell culture, single-molecule imaging confirms hexameric IL-5 complex formation on cell surfaces. Engineered chimeric receptors show that IL-5 signaling, as well as IL-3 and GM-CSF, can occur through receptor heterodimerization, obviating the need for higher-order assemblies of βc dimers. These findings provide insights into IL-5 and βc receptor family signaling mechanisms, aiding in the development of therapies for diseases involving deranged βc signaling.
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

The inability of neonates to develop CD4+FoxP3-CXCR5hiPD-1hi T follicular helper (TFH) cells contributes to their weak vaccine responses. In previous studies, we measured diminished IgG responses when IL-6 was co-injected with a pneumococcal conjugate vaccine (PCV) in neonatal mice. This is in sharp contrast to adults, where IL-6 improves vaccine responses by downregulating the expression of IL-2Rβ on TFH cells and protecting them from the inhibitory effect of IL-2. In this study, we found that splenic IL-6 levels rapidly increased in both adult and neonatal mice following immunization, but the increase in neonatal mice was significantly more than that of adult mice. Moreover, immunized neonatal TFH cells expressed significantly more IL-2 as well as its receptors, IL-2Rα and IL-2Rβ, than the adult cells. Remarkably, IL-6 co-injection with PCV vaccine further increased the production of IL-2 and the expression of its receptors by neonatal TFH cells, whereas excess IL-6 had totally opposite effect in immunized adult mice. Underscoring the role of IL-6 in activating the IL-2 mediated suppression of vaccine responses, immunization of IL-6 knock-out neonates led to improved antibody responses accompanied by expanded TFH cells as well as lower levels of IL-2 and IL-2 receptors on TFH cells. Moreover, CpG containing PCV improved TFH response in neonates by suppressing the expression of IL-2 receptors on TFH cells and inhibiting IL-2 activity. These findings unveil age-specific differences in IL-6 mediated vaccine responses and highlight the need to consider age-related immunobiological attributes in designing vaccines.
© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.