Mature dendritic cells (DCs) are known to activate effector immune responses, whereas steady state immature DCs can induce tolerance. Several studies have targeted immature murine quiescent DCs in vivo with antigen, including donor alloantigens, for the induction of tolerance. Receptors expressed by specific DC subsets have been also targeted with antibodies linked with antigens to induce tolerance; for instance, in vivo targeting of the DCIR2⁺ DC subset with donor alloantigen resulted in long-term survival of heart and skin transplants. DCs also express sialic acid immunoglobulin-like lectin (Siglec) receptors, and these have been successfully targeted with myelin oligiodendrocyte glycoprotein (MOG) antigen to induce tolerance in experimental autoimmune encephalomyelitis (EAE). We investigated, in a mismatched model of skin transplant (B6K^d into B6 recipient mice), whether targeting a sialylated alloantigen K^d (Sia-K^d) to Siglecs on recipient DCs promoted transplant survival. The injection of α2,3 Sia-K^d into B6 recipient mice prior to B6K^d skin transplantation, by binding to Batf3 dependent DCs, resulted in prolonged skin graft survival and an increase in CD4⁺CD62L⁺Foxp3⁺ Tregs. Targeting Siglecs on DC subsets in vivo represents a novel way of improving transplant survival.

Periodontitis is a chronic inflammatory disease characterized by alveolar bone loss driven by dysregulated immune responses. We previously showed that extracellular vesicles derived from retinoic acid-induced regulatory T lymphocytes (RA-Treg EVs) suppress pathogenic CD4⁺ T-lymphocyte responses and reduce alveolar bone loss during periodontitis. Herein, we investigated whether RA-Treg EVs also modulate macrophage and CD8⁺ T-lymphocyte responses during experimental periodontitis. Ligature-induced periodontitis was generated in mice, followed by local administration of RA-Treg EVs. Alveolar bone loss was analyzed by micro-computed tomography, and periodontal tissues and cervical lymph nodes were analyzed by flow cytometry to quantify antigen-presenting cells, macrophages, macrophage subsets, and CD8⁺ T lymphocytes. The direct effects of RA-Treg EVs on macrophage phenotype and CD8⁺ T-cell proliferation and activation were assessed in vitro. RA-Treg EV treatment attenuated alveolar bone loss and preserved trabecular microarchitecture. This effect was associated with reduced macrophage infiltration into periodontal tissues, modulation of macrophage polarization, and restoration of CD8⁺ T-cell abundance in periodontal tissues and draining cervical lymph nodes, without major changes in CD8⁺IFN-γ⁺ or CD8⁺RANKL⁺ cells. In vitro, RA-Treg EVs induced heterogeneous macrophage phenotypes distinct from the classical M1/M2 polarization states while markedly enhancing CD8⁺ T-cell proliferation and activation. These findings indicate that RA-Treg EVs preserve alveolar bone during experimental periodontitis while selectively modulating macrophage and CD8⁺ T-lymphocyte responses.

Cancer immunotherapy has reshaped modern medicine, providing new hope to patients by mobilizing the immune system to eliminate malignancies with potency and precision. While these therapies were originally designed to enhance immune responses against tumors, recent years have seen a transformative shift in the application of their underlying technology, with many of these pro-inflammatory and cytotoxic tools now being repurposed in a new array of diseases to achieve the opposite effect: immune tolerance. This research topic, Repurposing Cancer Immunotherapies for Use in Autoimmunity and Transplantation, brings together a collection of pioneering studies and reviews offering proof-of-concept studies, new mechanistic insights, and translational outlooks on how lessons learned from immuno-oncology are being repurposed to suppress, rather than stimulate, the immune system to establish tolerance in autoimmune disease, organ transplant rejection, graft-vs-host disease, and chronic inflammation. Reprogramming Tregs: Targeting Alloreactive B Cells and Lymphoid Niches Regulatory T cells (Tregs), a subset of CD4+ T cells dedicated to inhibiting immune responses and maintaining immune homeostasis, hold great promise as living therapeutics to establish immune tolerance in organ transplantation, graft-vs-host disease, and autoimmune disease [1; 2]. Two studies in this issue underscore the versatility of Tregs when armed with cancer therapy-inspired engineering strategies. One, by Ferreira and colleagues, introduces chimeric anti-HLA antibody receptor (CHAR) Tregs designed to suppress alloantigen-specific B cells in HLA sensitized transplant recipients (https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1601385/full). This elegant approach transforms Tregs into highly selective suppressors of anti-HLA-A2 B cells by equipping them with a synthetic receptor to recognize and inhibit these pathogenic antibody-producing cells. Importantly, CHAR Tregs remained non-cytotoxic and suppressed antibody production by HLA-A2 sensitized patient cells exposed to HLA-A2. This specificity could dramatically improve desensitization protocols in transplant medicine and extend the lifetime of organ transplants, moving beyond broad immunosuppression to precision targeting of harmful immune subsets. In the second study, Fousteri, Bonini, Biswas, and colleagues present CXCR5-engineered Tregs as a strategy to improve their localization and function in secondary and tertiary lymphoid tissues, aspects often overlooked in engineered cell therapies (https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1513009/full). In humanized mice, human Tregs co-expressing CXCR5 and an HLA-A2-specific chimeric antigen receptor (CAR) [3; 4; 5] trafficked to and persisted in transplanted HLA-A2 positive human pancreatic islets without impairing islet function, in line with previous studies [6]. Similarly, mouse Tregs co-expressing CXCR5 and a T cell receptor fusion construct (TRuC) against FVIII [7] displayed improved homing to and persistence in the spleen and lymph nodes, and suppressed anti-drug antibody (ADA) responses to recombinant FVIII protein to a greater extent than control FVIII TRuC Tregs in immunocompetent mice. These studies not only highlight the flexibility of Treg cell therapy but also emphasize the importance of molecular targeting, a key principle learned from CAR T cell therapy in oncology. Forging the Path to Precision Modeling of Autoimmune Disease Type 1 diabetes (T1D) is driven by the targeted immune destruction of insulin-producing β-cells, with CD8+ T cells playing a central pathogenic role. However, efforts to study these autoreactive T cells have been stymied by their rarity in the peripheral blood [8]. Brusko and colleagues address this challenge through innovative use of CRISPR/Cas9-mediated genome editing and lentiviral vector technology to reprogram the antigen specificity of primary human CD8+ T cells (https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1142648/full). By targeting the endogenous TCRα gene (TRAC) locus, these researchers generated HLA-A2-restricted islet peptide-specific CD8+ T cells that were cytotoxic towards HLA-A2 positive β-cells and secreted inflammatory cytokines. This work represents important progress not only on our ability to model autoimmunity more precisely, but also on preventing or even reversing it. Repurposing Cancer Drugs for Autoimmune Diseases Cancer therapeutics often exploit vulnerabilities in rapidly dividing cells – a characteristic shared by autoreactive immune cells. AZD6738, an ATR kinase inhibitor originally developed for oncologic indications [9], is now being investigated for T1D prevention. As reported in this research topic by Sugitani and colleagues, short-term treatment with AZD6738 prevents T1D and delays its onset in non-obese diabetic (NOD) mice by selectively depleting highly proliferative, self-reactive T cells (https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1290058/full#h13) . This strategy, if finetuned, can preferentially target autoaggressive cells while preserving overall immune competence. Similarly, dual inhibition of PI3Kδ and PI3Kγ, kinases often hyperactivated in B cell malignancies, shows promise in autoantibody-driven diseases like lupus. Marshall and colleagues show that Duvelisib, a PI3Kδ/γ inhibitor [10], significantly reduced B cell activation and autoantibody production, with associated improvements in kidney pathology, in the TAPP1R218LxTAPP2R211L PI3K pathway dysregulation-driven mouse model of lupus-like disease (https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1115244/full). Together, these exciting results suggest that drugs designed to inhibit tumor growth can be redirected to selectively eliminate pathogenic lymphocytes in autoimmunity. Towards a Broader...