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Introduction: The alarmin IL-33 has been implicated in the pathology of immune-mediated liver diseases. IL-33 activates regulatory T cells (Tregs) and type 2 innate lymphoid cells (ILC2s) expressing the IL-33 receptor ST2. We have previously shown that endogenous IL-33/ST2 signaling activates ILC2s that aggravate liver injury in murine immune-mediated hepatitis. However, treatment of mice with exogenous IL-33 before induction of hepatitis ameliorated disease severity. Since IL-33 induces expression of amphiregulin (AREG) crucial for Treg function, we investigated the immunoregulatory role of the ST2+ Treg/AREG axis in immune-mediated hepatitis. Methods: C57BL/6, ST2-deficient (Il1rl1-/-) and Areg-/- mice received concanavalin A to induce immune-mediated hepatitis. Foxp3Cre+ x ST2fl/fl mice were pre-treated with IL-33 before induction of immune-mediated hepatitis. Treg function was assessed by adoptive transfer experiments and suppression assays. The effects of AREG and IL-33 on ST2+ Tregs and ILC2s were investigated in vitro. Immune cell phenotype was analyzed by flow cytometry. Results and discussion: We identified IL-33-responsive ST2+ Tregs as an effector Treg subset in the murine liver, which was highly activated in immune-mediated hepatitis. Lack of endogenous IL-33 signaling in Il1rl1-/- mice aggravated disease pathology. This was associated with reduced Treg activation. Adoptive transfer of exogenous IL-33-activated ST2+ Tregs before induction of hepatitis suppressed inflammatory T-cell responses and ameliorated disease pathology. We further showed increased expression of AREG by hepatic ST2+ Tregs and ILC2s in immune-mediated hepatitis. Areg-/- mice developed more severe liver injury, which was associated with enhanced ILC2 activation and less ST2+ Tregs in the inflamed liver. Exogenous AREG suppressed ILC2 cytokine expression and enhanced ST2+ Treg activation in vitro. In addition, Tregs from Areg-/- mice were impaired in their capacity to suppress CD4+ T-cell activation in vitro. Moreover, application of exogenous IL-33 before disease induction did not protect Foxp3Cre+ x ST2fl/fl mice lacking ST2+ Tregs from immune-mediated hepatitis. In summary, we describe an immunoregulatory role of the ST2+ Treg/AREG axis in immune-mediated hepatitis, in which AREG suppresses the activation of hepatic ILC2s while maintaining ST2+ Tregs and reinforcing their immunosuppressive capacity in liver inflammation. [ABSTRACT FROM AUTHOR]

Influenza A virus (IAV) can cause severe respiratory infection leading to significant global morbidity and mortality through seasonal epidemics. Likewise, the constantly increasing number of cancer diseases is a growing problem. Nevertheless, the understanding of the mutual interactions of the immune responses between cancer and infection is still very vague. Therefore, it is important to understand the immunological cross talk between cancer and IAV infection. In several preclinical mouse models of cancer, including melanoma and colorectal cancer, we observed that IAV infection in the lung significantly decreased the tumour burden. Concomitantly, tumour-specific CD8+ T-cells are strongly activated upon infection, both in the tumour tissue and in the lung. CD8+ T-cell depletion during infection reverses the reduced tumour growth. Interestingly, IAV infection orchestrated the migration of tumour-specific CD8+ T-cells from the tumour into the infected lung. Blocking the migration of CD8+ T-cells prevented the anti-tumoural effect. Thus, our findings show that viral respiratory infection has significant impact on the anti-tumour CD8+ T-cell response, which will significantly improve our understanding of the immunological cross talk between cancer and infection. Author summary: The Influenza A virus (IAV) causes severe respiratory infections during seasonal outbreaks, while the rising incidence of cancer presents a growing health concern, yet our understanding of the interactions between immune responses to infection and cancer is still unclear. Therefore, we aimed to decipher the immunological cross talk between cancer and IAV infection. Using preclinical mouse models of melanoma and colorectal cancer, we made intriguing observations. IAV infection in the lung led to a significant reduction in tumour growth. Additionally, the infection activated tumour-specific CD8+ T-cells, crucial components of the immune system's cancer-fighting ability, both in the lung and tumour tissue. Remarkably, when CD8+ T-cells were depleted during infection, the tumour growth reduction was reversed. It appears that IAV infection orchestrates the migration of tumour-specific CD8+ T cells from the tumour into the infected lung, since blocking migration abolished the antitumor effect. These findings shed light on the significant impact of viral respiratory infection on the anti-tumour CD8+ T-cell response, advancing our understanding of the intricate interplay between cancer and infection. Such insights hold promise for tackling these complex health challenges more effectively. [ABSTRACT FROM AUTHOR]

Neuropilin-1 (Nrp-1) expression on CD8+ T cells has been identified in tumor-infiltrating lymphocytes and in persistent murine gamma-herpes virus infections, where it interferes with the development of long-lived memory T cell responses. In parasitic and acute viral infections, the role of Nrp-1 expression on CD8+ T cells remains unclear. Here, we demonstrate a strong induction of Nrp-1 expression on CD8+ T cells in Plasmodium berghei ANKA (PbA)-infected mice that correlated with neurological deficits of experimental cerebral malaria (ECM). Likewise, the frequency of Nrp-1+CD8+ T cells was significantly elevated and correlated with liver damage in the acute phase of lymphocytic choriomeningitis virus (LCMV) infection. Transcriptomic and flow cytometric analyses revealed a highly activated phenotype of Nrp-1+CD8+ T cells from infected mice. Correspondingly, in vitro experiments showed rapid induction of Nrp-1 expression on CD8+ T cells after stimulation in conjunction with increased expression of activation-associated molecules. Strikingly, T cell-specific Nrp-1 ablation resulted in reduced numbers of activated T cells in the brain of PbA-infected mice as well as in spleen and liver of LCMV-infected mice and alleviated the severity of ECM and LCMV-induced liver pathology. Mechanistically, we identified reduced blood-brain barrier leakage associated with reduced parasite sequestration in the brain of PbA-infected mice with T cell-specific Nrp-1 deficiency. In conclusion, Nrp-1 expression on CD8+ T cells represents a very early activation marker that exacerbates deleterious CD8+ T cell responses during both, parasitic PbA and acute LCMV infections. Author summary: Malaria is caused by the parasite Plasmodium and remains one of the most life threatening infectious diseases worldwide. In 2021, WHO reported 247 million malaria cases and more than 600,000 deaths. In this study, we infect mice with Plasmodium berghei ANKA (PbA), a scientific model of experimental cerebral malaria (ECM), which affects the brain and is often fatal. During infection, CD8+ T cells are known to invade the brain and contribute to brain damage and inflammation through their activated and cytotoxic potential. We investigate whether T cell-expressed Neuropilin-1 (Nrp-1), a co-receptor for semaphorin and vascular endothelial growth factor (VEGF) known to play a role in immune cell activation and migration, has an impact on ECM manifestation. The results of our study demonstrate that Nrp-1 is associated with increased T cell activation and significantly aggravates the severity of ECM. Importantly, our results are also applicable to other CD8+ T cell-induced immunopathologies as we show similar effects during lymphocytic choriomeningitis virus (LCMV) infection. Together, this implies that Nrp-1 may be an early prognostic marker and blockade of Nrp-1 could be a promising target to control exacerbated T cell responses in different diseases. [ABSTRACT FROM AUTHOR]