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Lassa fever, a viral hemorrhagic fever caused by the arenavirus Lassa virus (LASV), affects thousands of individuals annually, highlighting the need for a vaccine. Yet, immunological correlates of viral load control remain poorly defined. Here we study vaccination-induced immunity in a surrogate LASV challenge model in mice. We find that LASV-cross-reactive B cell immunity induced by the glycoprotein of distantly related arenaviruses, such as lymphocytic choriomeningitis virus (LCMV), provides significant viral load control. Counter to common concepts, suppression of viremia is observed in the absence of CD8 T cells or neutralizing antibodies but correlates with non-neutralizing glycoprotein-specific antibody responses. Adoptive cell transfer experiments with monoclonal LCMV-specific B cells demonstrates that these cells suppress viral loads when previously activated by a heterologous cross-reactive glycoprotein and diversified by somatic hypermutation. These findings establish vaccination-induced B cell immunity to the LASV glycoprotein as a correlate of viral load control, independently of virus-neutralizing antibody titers at the time of challenge. Lassa virus is a key pathogen that can cause haemorrhagic fever and further understanding of successful therapeutic strategies are needed. Here the authors explore the use of a Lassa virus glycoprotein-based vaccine and show B cell immunity as a correlate of protection in a mouse model of vaccination and subsequent viral challenge

Viral infections lead to alarmin release and elicit potent cytotoxic effector T lymphocyte (CTL eff ) responses. Conversely, the induction of protective tumour-specific CTL eff and their recruitment into the tumour remain challenging tasks. Here we show that lymphocytic choriomeningitis virus (LCMV) can be engineered to serve as a replication competent, stably-attenuated immunotherapy vector (artLCMV). artLCMV delivers tumour-associated antigens to dendritic cells for efficient CTL priming. Unlike replication-deficient vectors, artLCMV targets also lymphoid tissue stroma cells expressing the alarmin interleukin-33. By triggering interleukin-33 signals, artLCMV elicits CTL eff responses of higher magnitude and functionality than those induced by replication-deficient vectors. Superior anti-tumour efficacy of artLCMV immunotherapy depends on interleukin-33 signalling, and a massive CTL eff influx triggers an inflammatory conversion of the tumour microenvironment. Our observations suggest that replicating viral delivery systems can release alarmins for improved anti-tumour efficacy. These mechanistic insights may outweigh safety concerns around replicating viral vectors in cancer immunotherapy. Viruses trigger potent cytotoxic T cell responses, whereas anti-tumour immunity has been difficult to establish. Here the authors engineer a replicating viral delivery system for tumour-associated antigens, which induces alarmin release, innate activation and protective anti-tumour immunity in mice.

The tumor microenvironment (TME) is a complex amalgam of tumor cells, immune cells, endothelial cells and fibroblastic stromal cells (FSC). Cancer-associated fibroblasts are generally seen as tumor-promoting entity. However, it is conceivable that particular FSC populations within the TME contribute to immune-mediated tumor control. Here, we show that intratumoral treatment of mice with a recombinant lymphocytic choriomeningitis virus-based vaccine vector expressing a melanocyte differentiation antigen resulted in T cell-dependent long-term control of melanomas. Using single-cell RNA-seq analysis, we demonstrate that viral vector-mediated transduction reprogrammed and activated a Cxcl13 -expressing FSC subset that show a pronounced immunostimulatory signature and increased expression of the inflammatory cytokine IL-33. Ablation of Il33 gene expression in Cxcl13-Cre-positive FSCs reduces the functionality of intratumoral T cells and unleashes tumor growth. Thus, reprogramming of FSCs by a self-antigen-expressing viral vector in the TME is critical for curative melanoma treatment by locally sustaining the activity of tumor-specific T cells. Lymphocytic choriomeningitis virus (LCMV)-based viral vectors have been shown to induce potent antitumor immune responses. Here the authors show that a LCMV-based vaccine vector remodels the tumor-associated fibroblastic stroma, sustaining CD8+ T cell activation and reducing tumor growth in a preclinical model of melanoma.

The responses of CD8 + T cells to hepatotropic viruses such as hepatitis B range from dysfunction to differentiation into effector cells, but the mechanisms that underlie these distinct outcomes remain poorly understood. Here we show that priming by Kupffer cells, which are not natural targets of hepatitis B, leads to differentiation of CD8 + T cells into effector cells that form dense, extravascular clusters of immotile cells scattered throughout the liver. By contrast, priming by hepatocytes, which are natural targets of hepatitis B, leads to local activation and proliferation of CD8 + T cells but not to differentiation into effector cells; these cells form loose, intravascular clusters of motile cells that coalesce around portal tracts. Transcriptomic and chromatin accessibility analyses reveal unique features of these dysfunctional CD8 + T cells, with limited overlap with those of exhausted or tolerant T cells; accordingly, CD8 + T cells primed by hepatocytes cannot be rescued by treatment with anti-PD-L1, but instead respond to IL-2. These findings suggest immunotherapeutic strategies against chronic hepatitis B infection. CD8 + T cells that are primed by hepatocytes differentiate into dysfunctional T cells, which can be rescued by treatment with IL-2.

Significance The alarmin IL-33 amplifies immune responses of Th2 and CD8 ⁺ cytotoxic T cells against invading pathogens; however, little is known about a potential role of IL-33 in Th1 cell responses. This study demonstrates that activated Th1 effector cells transiently express the IL-33 receptor ST2 upon differentiation in vitro and in vivo during viral infection. ST2 expression on virus-specific Th1 cells depended on the Th1-associated transcription factors T-bet and STAT4. ST2-deficient virus-specific CD4 ⁺ T cells showed impaired expansion and Th1 effector function upon viral infection, indicating a direct impact of IL-33 on antiviral Th1 cell responses. These observations redefine the role of ST2 in Th cell activation, with implications for the design of adjuvants and therapies targeting the IL-33–ST2 pathway. During infection, the release of damage-associated molecular patterns, so-called “alarmins,” orchestrates the immune response. The alarmin IL-33 plays a role in a wide range of pathologies. Upon release, IL-33 signals through its receptor ST2, which reportedly is expressed only on CD4 ⁺ T cells of the Th2 and regulatory subsets. Here we show that Th1 effector cells also express ST2 upon differentiation in vitro and in vivo during lymphocytic choriomeningitis virus (LCMV) infection. The expression of ST2 on Th1 cells was transient, in contrast to constitutive ST2 expression on Th2 cells, and marked highly activated effector cells. ST2 expression on virus-specific Th1 cells depended on the Th1-associated transcription factors T-bet and STAT4. ST2 deficiency resulted in a T-cell–intrinsic impairment of LCMV-specific Th1 effector responses in both mixed bone marrow-chimeric mice and adoptive cell transfer experiments. ST2-deficient virus-specific CD4 ⁺ T cells showed impaired expansion, Th1 effector differentiation, and antiviral cytokine production. Consequently, these cells mediated little virus-induced immunopathology. Thus, IL-33 acts as a critical and direct cofactor to drive antiviral Th1 effector cell activation, with implications for vaccination strategies and immunotherapeutic approaches.

When small protein fragments or nucleic acids derived from an invading pathogen are detected by pattern recognition receptors on immune cells, the innate immune response is triggered. This event activates cells of the adaptive immune system, and together, both responses clear the infection. Infections also induce the release of “danger-associated molecular patterns,” or alarmins, from the host as a result of tissue damage. Whether these are also important for the ensuing immune response is less clear. Bonilla et al. (p. 984 , published online 2 February) report that the alarmin, interleukin-33, is required for optimal cytotoxic CD8 + T cells responses and antiviral immunity in mice. In virus-infected mice deficient in IL-33 or its receptor, IL-33 is essential for signaling CD8 + T cells to expand, produce multiple cytokines and acquire cytotoxic capabilities. These results showed that endogenous material, independently of pathogen-derived molecules, are also required for antiviral immunity. A danger signal released from dying cells is required for antiviral immunity in mice. Pathogen-associated molecular patterns decisively influence antiviral immune responses, whereas the contribution of endogenous signals of tissue damage, also known as damage-associated molecular patterns or alarmins, remains ill defined. We show that interleukin-33 (IL-33), an alarmin released from necrotic cells, is necessary for potent CD8 + T cell (CTL) responses to replicating, prototypic RNA and DNA viruses in mice. IL-33 signaled through its receptor on activated CTLs, enhanced clonal expansion in a CTL-intrinsic fashion, determined plurifunctional effector cell differentiation, and was necessary for virus control. Moreover, recombinant IL-33 augmented vaccine-induced CTL responses. Radio-resistant cells of the splenic T cell zone produced IL-33, and efficient CTL responses required IL-33 from radio-resistant cells but not from hematopoietic cells. Thus, alarmin release by radio-resistant cells orchestrates protective antiviral CTL responses.

Rare cases of stable allograft acceptance after discontinuation of immunosuppression are often accompanied by macrochimerism (> 1% donor cells in blood) or microchimerism (< 1% donor cells in blood). Here, we have investigated whether persistence of donor cells is the cause or the consequence of long-lasting CTL unresponsiveness. We found that engraftment of splenocytes bearing a single foreign MHC class I-restricted epitope resulted in lifelong donor cell microchimerism and specific CTL unresponsiveness. This status was reversed in a strictly time- and thymus-dependent fashion when the engrafted cells were experimentally removed. The results presented herein show that microchimerism actively maintains CTL unresponsiveness toward a minor histocompatibility antigen by deleting the specific repertoire and thus excluding dominant, T cell extrinsic mechanisms of CTL unresponsiveness independent of systemically persisting donor cell antigen.

Pathogen-associated molecular patterns decisively influence antiviral immune responses, whereas the contribution of endogenous signals of tissue damage, also known as damage-associated molecular patterns or alarmins, remains ill defined. We show that interleukin-33 (IL-33), an alarmin released from necrotic cells, is necessary for potent CD8 + T cell (CTL) responses to replicating, prototypic RNA and DNA viruses in mice. IL-33 signaled through its receptor on activated CTLs, enhanced clonal expansion in a CTL-intrinsic fashion, determined plurifunctional effector cell differentiation, and was necessary for virus control. Moreover, recombinant IL-33 augmented vaccine-induced CTL responses. Radio-resistant cells of the splenic T cell zone produced IL-33, and efficient CTL responses required IL-33 from radio-resistant cells but not from hematopoietic cells. Thus, alarmin release by radio-resistant cells orchestrates protective antiviral CTL responses.

Rare cases of stable allograft acceptance after discontinuation of immunosuppression are often accompanied by macrochimerism (> 1% donor cells in blood) or microchimerism (< 1% donor cells in blood). Here, we have investigated whether persistence of donor cells is the cause or the consequence of long-lasting CTL unresponsiveness. We found that engraftment of splenocytes bearing a single foreign MHC class I-restricted epitope resulted in lifelong donor cell microchimerism and specific CTL unresponsiveness. This status was reversed in a strictly time- and thymus-dependent fashion when the engrafted cells were experimentally removed. The results presented herein show that microchimerism actively maintains CTL unresponsiveness toward a minor histocompatibility antigen by deleting the specific repertoire and thus excluding dominant, T cell extrinsic mechanisms of CTL unresponsiveness independent of systemically persisting donor cell antigen.