European Journal of Immunology最新文献

Antibody feedback in germinal center (GC) responses plays a key role in shaping the affinity, specificity, and longevity of humoral immunity. Beyond neutralizing pathogens, antibodies influence B cell selection by modulating antigen availability and masking dominant epitopes, thereby reshaping the competitive landscape for T follicular helper (Tfh) cell support. This review outlines the current understanding of how antibody feedback governs the selection stringency and clonal evolution of GC B cells, facilitates and promotes the emergence of epitope spread, and contributes to GC shutdown. We also examine how it supports the development of broadly neutralizing antibodies. Finally, we discuss how these insights are informing next-generation vaccine strategies—including immunogen design, prime-boost regimens, and adjuvant optimization—to guide affinity maturation toward specific epitopes and overcome feedback-driven constraints. Understanding antibody feedback not only reveals fundamental principles of adaptive immunity but also offers new avenues for rational vaccine design and therapeutic immune modulation.

Group 3 innate lymphoid cells (ILC3s) are tissue-resident lymphocytes distributed across both lymphoid and non-lymphoid tissues, capable of mounting rapid immune responses. They are defined by expression of the transcription factor RORγt and comprise distinct subsets, including lymphoid tissue inducer-like cells expressing major histocompatibility complex class II (MHCII). These MHCII⁺ ILC3s can directly present antigens to CD4⁺ T cells, a function regulated by the transcriptional activator CIITA through a pathway similar to thymic epithelial cells. ILC3s contribute to immune homeostasis by limiting effector T cell responses and promoting regulatory T cell differentiation. However, under the influence of distinct cytokine milieus, such as IL-1β and IFN-γ, ILC3s undergo a maturation process, upregulating costimulatory molecules and enhancing their antigen-presenting capacity to activate CD4⁺ T cells. This dual functionality is highly plastic and influenced by tissue-specific environmental cues, enabling ILC3s to adapt their immunoregulatory roles according to local context. Overall, ILC3s now emerge as critical modulators of T cell activities, balancing tolerance and activation, with significant implications for host defense, autoimmunity, inflammation, and cancer.

Selecting a sensitive test system is crucial to measure IFNα in serum samples. Simoa digital ELISA stands out for its high sensitivity and strong correlation with transcript-based IFN-induced gene (ISG) scores. In SLE, the ISG score is explained by circulating IFNα levels with negligible contribution from IFNβ or IFNγ. Created in BioRender.

The stimulator of interferon genes (STING) pathway plays a pivotal role in innate immunity, acting as a key sensor of cytosolic DNA to initiate type-I Interferon (IFN) and pro-inflammatory cytokine production. This pathway is essential for host defence against bacterial, viral and other pathogenic threats and has emerged as a promising therapeutic target in cancer immunotherapy. However, conventional techniques such as immunoblotting and qPCR are limited in their capacity to study STING pathway activation in complex and heterogeneous biological systems, such as tumour masses or large cell populations. Here, we describe the application of mass cytometry (CyTOF) as a cutting-edge approach to characterize the STING pathway at the sub-population level. Using a high-dimensional panel of metal-labelled antibodies targeting key STING signalling components, we achieved resolution of pathway activation across diverse immune cell populations. This approach promises novel insights into cellular heterogeneity, pathway dynamics and the interplay between STING signalling and other immune pathways and underscores the power of high-dimensional analysis to overcome the limitations of traditional methods to enable a more comprehensive exploration of immune signalling pathways.

Tissue-resident and recruited macrophages are integral to organ development, homeostasis, immunity, and disease pathogenesis. Their remarkable diversity arises from distinct developmental origins, differentiation trajectories, and microenvironmental cues that shape their identity and function. Central to these processes is transcriptional regulation. In this review, we provide a comprehensive overview of the transcription factor (TF) networks that orchestrate resident tissue macrophage (RTM) differentiation from progenitor cells, imprint core macrophage identity, and drive tissue-specific functions. We first delineate the collaborative roles of lineage-determining TFs, such as PU.1 and C/EBPs, which prime macrophage progenitors for commitment. We then examine identity-imprinting TFs that establish and maintain the core macrophage program, and tissue-specific TFs that allow integration of local niche signals to tailor RTM phenotypes across organs. While the focus is on RTMs at steady state, we also highlight how RTMs can undergo transcriptional reprogramming upon tissue perturbation, and how newly recruited macrophages may engage distinct regulatory circuits upon entering diseased tissues, with tumors serving as an example.

Graft-versus-host disease is mediated by donor-derived T cells reactive against the recipient's broadly expressed minor histocompatibility antigens (mHA). Regulatory T cells (Treg) have been explored as a therapeutic approach for chronic GVHD (cGVHD). The promising results from polyclonal Treg trials in this setting have led us to develop a Treg product specific for mismatched minor antigens between patient and donor (mTreg), circumventing broad immune suppression risks. HLA-matched siblings of opposite sexes were used to obtain the sister's CD4⁺CD25^hiCD127^low Treg for co-culture with the respective brother's dendritic cells as a source of mismatched mHA. We have established the optimal culture conditions resulting in the highest mTreg proliferation and viability. Comprehensive phenotyping during the ex vivo selection shows PD-1, CTLA-4, CD39 and HLA-DR expression. Transcriptomic analysis revealed a switch in metabolic process, and up-regulation of functional Treg genes. Furthermore, mTreg possess specific and potent suppressive activity, in which there is a dependency on cell-to-cell contact and a role for HLA class II expression on mTreg. This protocol would allow the generation of Treg specific to an array of mHA from the recipient's healthy tissues, likely providing a directed and strong suppression of cGVHD.

Natural clearance of hepatitis C virus (HCV) infection occurs in about 25% of primary infections, but offers only partial protective immunity against re-infections. This study hypothesised that long-lived polyfunctional HCV-specific CD8+ memory stem T cells (T_SCM) contribute to protective immunity in rare super-clearer subjects who repeatedly clear viraemia. Six super-clearers and four clearer-chronic subjects who resolved a primary infection but subsequently developed chronic infection were studied at multiple timepoints. The T_SCM population (CCR7+CD45RA+CD95+) was bulk sorted, labelled with CellTrace Violet (CTV), and stimulated in vitro for five days with cognate HCV peptide, IL-2/IL-15, and autologous PBMCs. Functionality of the expanded HCV-specific T_SCM was assessed via the proliferation, multi-potency, and stemness indices. Total HCV-specific CD8+ T cells from super-clearers exhibited enhanced proliferative recall capability compared with clearer-chronics. Furthermore, super-clearers exhibited higher HCV-T_SCM frequencies post-expansion (22.35 ± 34.35 vs. 2.41 ± 9.83; p = 0.0066). Notably, HCV-T_SCM in clearer-chronics had ‘stemness’ indices of zero in samples before the re-infection (i.e., no ability to generate T_SCM as progeny), whereas super-clearers consistently retained this key functional property. These findings suggest that the maintenance of self-renewing HCV-specific T_SCM may underpin long-term protective immunity against re-infection and could inform vaccine design strategies targeting durable cellular memory.

Type 1 and type 2 diabetes are associated with increased severity and mortality from respiratory virus infections. Vaccination in the general population significantly reduces the risk of severe respiratory viral infection and triggers a strong, polyfunctional, and lasting T cell response in healthy individuals. However, vaccine effectiveness in people with type 1 diabetes is unclear. Here, we studied the magnitude and functional characteristics of vaccine-specific CD4⁺ and CD8⁺ T cell responses to vaccination in people with type 1 and type 2 diabetes and compared them to those of people living without diabetes, using the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine as a model. We found defects in both CD4⁺ and CD8⁺ T cell memory maintenance and the functionality of the vaccine-specific T cells in people with diabetes compared with people without. In those individuals with type 1 and type 2 diabetes who harbored detectable vaccine-specific T cells, they displayed an unfocused, tolerogenic phenotype characterized by increased expression of IL-10 and IL-13 compared with people without diabetes. These results have implications for vaccination strategies for people with diabetes.