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BACKGROUND: Asthma is an incurable heterogeneous disease with variations in clinical and underlying immunological phenotype. New approaches could help to support existing therapy concepts. Neonatal infection of mice with Helicobacter pylori or administration of H. pylori-derived extracts or molecules after birth have been shown to prevent the development of allergic airway disease later in life. This study evaluated the potential therapeutic efficacy of H. pylori vacuolating cytotoxin A (VacA) in allergic airway inflammation and investigated the underlying immunological mechanisms for its actions. METHODS: Murine models of allergic airway diseases, and murine and human in vitro models were used. RESULTS: In both an acute model and a therapeutic house dust mite model of allergic airway disease, treatment with H. pylori-derived VacA reduced several asthma hallmarks, including airway hyperresponsiveness, inflammation and goblet cell metaplasia. Flow cytometry and ELISA analyses revealed induction of tolerogenic dendritic cells (DC) and FoxP3 positive regulatory T cells (Tregs), and a shift in the composition of allergen-specific immunoglobulins. Depletion of Tregs during treatment with VacA reversed treatment-mediated suppression of allergic airway disease. Human monocyte derived DCs (moDC) that were exposed to VacA induced Tregs in co-cultured naïve autologous T cells, replicating key observations made in vivo. CONCLUSION: H. pylori-derived VacA suppressed allergic airway inflammation via induction of Tregs in both allergic airway disease models. These data suggest that the immunomodulatory activity of VacA could potentially be exploited for the prevention and treatment of allergic airway disease.

Decline in immune function during aging increases susceptibility to different aging‐related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance of naïve/memory T‐cell subpopulations, still remain largely elusive. Here, we show that loss of DJ‐1 encoded by PARK7/DJ‐1, causing early‐onset familial Parkinson’s disease (PD), unexpectedly diminished signs of immunoaging in T‐cell compartments of both human and mice. Compared with two gender‐matched unaffected siblings of similar ages, the index PD patient with DJ‐1 deficiency showed a decline in many critical immunoaging features, including almost doubled non‐senescent T cells. The observation was further consolidated by the results in 45‐week‐old DJ‐1 knockout mice. Our data demonstrated that DJ‐1 regulates several immunoaging features via hematopoietic‐intrinsic and naïve‐CD8‐intrinsic mechanisms. Mechanistically, DJ‐1 depletion reduced oxidative phosphorylation (OXPHOS) and impaired TCR sensitivity in naïve CD8 T cells at a young age, accumulatively leading to a reduced aging process in T‐cell compartments in older mice. Our finding suggests an unrecognized critical role of DJ‐1 in regulating immunoaging, discovering a potent target to interfere with immunoaging‐ and aging‐associated diseases.

Decline in immune function during aging increases susceptibility to different aging‐related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance of naïve/memory T‐cell subpopulations, still remain largely elusive. Here, we show that loss of DJ‐1 encoded by PARK7/DJ‐1, causing early‐onset familial Parkinson’s disease (PD), unexpectedly diminished signs of immunoaging in T‐cell compartments of both human and mice. Compared with two gender‐matched unaffected siblings of similar ages, the index PD patient with DJ‐1 deficiency showed a decline in many critical immunoaging features, including almost doubled non‐senescent T cells. The observation was further consolidated by the results in 45‐week‐old DJ‐1 knockout mice. Our data demonstrated that DJ‐1 regulates several immunoaging features via hematopoietic‐intrinsic and naïve‐CD8‐intrinsic mechanisms. Mechanistically, DJ‐1 depletion reduced oxidative phosphorylation (OXPHOS) and impaired TCR sensitivity in naïve CD8 T cells at a young age, accumulatively leading to a reduced aging process in T‐cell compartments in older mice. Our finding suggests an unrecognized critical role of DJ‐1 in regulating immunoaging, discovering a potent target to interfere with immunoaging‐ and aging‐associated diseases.

Therapeutic promotion of intestinal regeneration holds great promise, but defining the cellular mechanisms that influence tissue regeneration remains an unmet challenge. To gain insight into the process of mucosal healing, we longitudinally examined the immune cell composition during intestinal damage and regeneration. B cells were the dominant cell type in the healing colon, and single-cell RNA sequencing (scRNA-seq) re-vealed expansion of an IFN-induced B cell subset during experimental mucosal healing that predominantly located in damaged areas and associated with colitis severity. B cell depletion accelerated recovery upon injury, decreased epithelial ulceration, and enhanced gene expression programs associated with tissue re-modeling. scRNA-seq from the epithelial and stromal compartments combined with spatial transcriptomics and multiplex immunostaining showed that B cells decreased interactions between stromal and epithelial cells during mucosal healing. Activated B cells disrupted the epithelial-stromal cross talk required for orga-noid survival. Thus, B cell expansion during injury impairs epithelial-stromal cell interactions required for mucosal healing, with implications for the treatment of IBD., QC 20230301

The glycoprotein CD83 is known to be expressed by different immune cells including activated CD4(+) Foxp3(+) regulatory T cells (Tregs) and CD4(+) Foxp3(-) conventional T cells. However, the physiological function of endogenous CD83 in CD4(+) T cell subsets is still unclear. In this study, we have generated a new CD83(flox) mouse line on BALB/c background, allowing for specific ablation of CD83 in T cells upon breeding with CD4-cre mice. Tregs from CD8(flox/flox)/CD4-cre(tg/wt) mice had similar suppressive activity as Tregs from CD83(flox/flox)/CD4-cre(wt/wt) wild-type littermates, suggesting that endogenous CD83 expression is dispensable for the inhibitory capacity of Tregs. However, CD83-deficient CD4(+) conventional T cells showed elevated proliferation and IFN-gamma secretion as well as an enhanced capacity to differentiate into Th1 cells and Th17 cells upon stimulation in vitro. T cell-specific ablation of CD83 expression resulted in aggravated contact hypersensitivity reaction accompanied by enhanced CD4(+) T cell activation. Moreover, adoptive transfer of CD4(+) CD45RB(high) T cells from CD83(flox/flox)/CD4-cre(tg/wt) mice into Rag2-deficient mice elicited more severe colitis associated with increased serum concentrations of IL-12 and elevated CD40 expression on CD11c(+) dendritic cells (DCs). Strikingly, DCs from BALB/c mice cocultured with CD83-deficient CD4(+) conventional T cells showed enhanced CD40 expression and IL-12 secretion compared with DCs cocultured with CD4(+) conventional T cells from CD83(flox/flox)/CD4-cre(wt/wt) wild-type mice. In summary, these results indicate that endogenous CD83 expression in CD4(+) conventional T cells plays a crucial role in controlling CD4(+) T cell responses, at least in part, by regulating the activity of CD11c(+) DCs.

The glycoprotein CD83 is known to be expressed by different immune cells including activated CD4(+) Foxp3(+) regulatory T cells (Tregs) and CD4(+) Foxp3(-) conventional T cells. However, the physiological function of endogenous CD83 in CD4(+) T cell subsets is still unclear. In this study, we have generated a new CD83(flox) mouse line on BALB/c background, allowing for specific ablation of CD83 in T cells upon breeding with CD4-cre mice. Tregs from CD8(flox/flox)/CD4-cre(tg/wt) mice had similar suppressive activity as Tregs from CD83(flox/flox)/CD4-cre(wt/wt) wild-type littermates, suggesting that endogenous CD83 expression is dispensable for the inhibitory capacity of Tregs. However, CD83-deficient CD4(+) conventional T cells showed elevated proliferation and IFN-gamma secretion as well as an enhanced capacity to differentiate into Th1 cells and Th17 cells upon stimulation in vitro. T cell-specific ablation of CD83 expression resulted in aggravated contact hypersensitivity reaction accompanied by enhanced CD4(+) T cell activation. Moreover, adoptive transfer of CD4(+) CD45RB(high) T cells from CD83(flox/flox)/CD4-cre(tg/wt) mice into Rag2-deficient mice elicited more severe colitis associated with increased serum concentrations of IL-12 and elevated CD40 expression on CD11c(+) dendritic cells (DCs). Strikingly, DCs from BALB/c mice cocultured with CD83-deficient CD4(+) conventional T cells showed enhanced CD40 expression and IL-12 secretion compared with DCs cocultured with CD4(+) conventional T cells from CD83(flox/flox)/CD4-cre(wt/wt) wild-type mice. In summary, these results indicate that endogenous CD83 expression in CD4(+) conventional T cells plays a crucial role in controlling CD4(+) T cell responses, at least in part, by regulating the activity of CD11c(+) DCs.

Dendritic cells (DCs) are highly specialized antigen-presenting cells that orchestrate adaptive immune responses to pathogens. During malaria infection pro- and anti-inflammatory T cell responses have to be tightly balanced to ensure parasite clearance without induction of severe immune pathologies. However, the precise role of CD11chigh DCs in this process is still discussed controversially. Here, we demonstrate that long-term depletion of conventional CD11chigh DCs in Plasmodium yoelii (P. yoelii)-infected diphtheria toxin (DT)-treated RosaiDTR/CD11c-cre mice interferes with the activation of CD8+ and CD4+ T cells as well as CD4+Foxp3+ regulatory T cells at early time points during infection. Moreover, systemic levels of the pro-inflammatory cytokines IFN-γ and TNF-α were decreased in P. yoelii-infected mice deficient for CD11chigh DCs compared to infected RosaiDTR controls. To further elucidate the importance of CD11chigh DCs during the later phase of infection, we treated RosaiDTR/CD11c-cre and control mice with DT only from day 4 of P. yoelii infection onward. Strikingly, this approach had no impact on the activation and IFN-γ production of CD4+ and CD8+ effector T cells. These results indicate that CD11chigh DCs play a crucial role in eliciting effector T cell responses during the initial phase, but are dispensable during ongoing infection with P. yoelii., Peer Reviewed

The aryl hydrocarbon receptor ( AHR) is a ligand- dependent transcription factor best known for mediating the toxicity of dioxin(1). Environmental factors are believed to contribute to the increased prevalence of autoimmune diseases, many of which are due to the activity of T(H)17 T cells, a new helper T- cell subset characterized by the production of the cytokine IL- 17. Here we show that in the CD4(+) T- cell lineage of mice AHR expression is restricted to the T(H)17 cell subset and its ligation results in the production of the T(H)17 cytokine interleukin ( IL)- 22. AHR is also expressed in human T(H)17 cells. Activation of AHR by a high-affinity ligand during T(H)17 cell development markedly increases the proportion of T(H)17 T cells and their production of cytokines. CD4(+) T cells from AHR- deficient mice can develop T(H)17 cell responses, but when confronted with AHR ligand fail to produce IL- 22 and do not show enhanced T(H)17 cell development. AHR activation during induction of experimental autoimmune encephalomyelitis causes accelerated onset and increased pathology in wild- type mice, but not AHR- deficient mice. AHR ligands may therefore represent co- factors in the development of autoimmune diseases.