Variants of the Bach2 gene are linked to vitiligo, celiac disease and type I diabetes, but the underlying immunological mechanisms are unknown. Here, we demonstrate that Bach2 plays crucial roles in maintaining T cell quiescence, and governing the differentiation, activation, and survival of foxp3+ Treg cells. Bach2-deficient T cells display spontaneous activation and produce elevated levels of TH1/TH2 type cytokines. Without Bach2, Treg cells exhibit diminished foxp3 expression, depleted numbers, hyper-activation, enhanced proliferation and profound loss of competitive fitness in vivo. Mechanistically, reduced survival of Bach2-deficient Treg cells was associated with reduced Bcl-2 and Mcl-1 levels and elevated Bim:Bcl-2 ratio. Additionally, Bach2 deficiency induced selective loss of Helios− foxp3+ Treg cells and a Treg cell transcriptome skewed towards the TH1/TH2 effector program at the expense of the Treg program. In vitro experiments confirmed that Bach2: (1) is indispensable for TCR/TGF-β-induced foxp3 expression and (2) mitigates aberrant differentiation of Treg cells by repression of the competing Gata3-driven TH2 effector program. Importantly, perturbations in the differentiation of induced Treg cells was linked to a fatal TH2 type chronic inflammatory lung disease in Bach2-deficient mice. Thus, Bach2 enforces T cell quiescence, promotes the development and survival of Treg lineage, restrains aberrant differentiation of Treg cells and protects against immune -mediated diseases.

Vaccines may help reduce the growing incidence of fungal infections in immune-suppressed patients. We have found that, even in the absence of CD4+ T-cell help, vaccine-induced CD8+ T cells persist and confer resistance against Blastomyces dermatitidis and Histoplasma capsulatum. Type 1 cytokines contribute to that resistance, but they also are dispensable. Although the role of T helper 17 cells in immunity to fungi is debated, IL-17 producing CD8+ T cells (Tc17 cells) have not been investigated. Here, we show that Tc17 cells are indispensable in antifungal vaccine immunity in hosts lacking CD4+ T cells. Tc17 cells are induced upon vaccination, recruited to the lung on pulmonary infection, and act non-redundantly in mediating protection in a manner that requires neutrophils. Tc17 cells did not influence type I immunity, nor did the lack of IL-12 signaling augment Tc17 cells, indicating a distinct lineage and function. IL-6 was required for Tc17 differentiation and immunity, but IL-1R1 and Dectin-1 signaling was unexpectedly dispensable. Tc17 cells expressed surface CXCR3 and CCR6, but only the latter was essential in recruitment to the lung. Although IL-17 producing T cells are believed to be short-lived, effector Tc17 cells expressed low levels of KLRG1 and high levels of the transcription factor TCF-1, predicting their long-term survival and stem-cell like behavior. Our work has implications for designing vaccines against fungal infections in immune suppressed patients.

The domestic ferret (Mustela putorius furo) is an important animal model for multiple human respiratory diseases. It is considered the ‘gold standard’ for modeling human influenza virus infection and transmission1–4. Here we describe the 2.41 Gb draft genome assembly of the domestic ferret, constituting 2.28 Gb of sequence plus gaps. We annotate 19,910 protein-coding genes on this assembly using RNA-seq data from 21 ferret tissues. We characterize the ferret host response to two influenza virus infections by RNA-seq analysis of 42 ferret samples from influenza time courses, and show distinct signatures in ferret trachea and lung tissues specific to 1918 or 2009 human pandemic influenza virus infections. Using microarray data from 16 ferret samples reflecting cystic fibrosis (CF) disease progression, we show that transcriptional changes in the CFTR-knockout ferret lung reflect pathways of early disease that cannot be readily studied in human infants with CF disease.

Immunologic memory is the adaptive immune system's powerful ability to remember a previous antigen encounter and react with accelerated vigor upon antigen re-exposure. It provides durable protection against reinfection with pathogens and is the foundation for vaccine-induced immunity. Unlike the relatively restricted immunologic purview of memory B cells and CD8 T cells, the field of CD4 T-cell memory must account for multiple distinct lineages with diverse effector functions, the issue of lineage commitment and plasticity, and the variable distribution of memory cells within each lineage. Here, we discuss the evidence for lineage-specific CD4 T-cell memory and summarize the known factors contributing to memory-cell generation, plasticity, and long-term maintenance.

SUMMARY Pandemic influenza viruses modulate pro-inflammatory responses that can lead to immunopathogenesis. We present an extensive and systematic profiling of lipids, metabolites and proteins in respiratory compartments of ferrets infected with either 1918 or 2009 human pandemic H1N1 influenza viruses. Integrative analysis of high-throughput omics data with virologic and histopathologic data uncovered relationships between host responses and phenotypic outcomes of viral infection. Pro-inflammatory lipid precursors in the trachea following 1918 infection correlated with severe tracheal lesions. Using an algorithm to infer cell quantity changes from gene expression data, we found enrichment of distinct T cell subpopulations in the trachea. There was also a predicted increase in inflammatory monocytes in the lung of 1918 virus-infected animals that was sustained throughout infection. This study presents a unique resource to the influenza research community and demonstrates the utility of an integrative systems approach for characterization of lipid metabolism alterations underlying respiratory responses to viruses.

Significance Immunity induced by the first-generation COVID-19 vaccines may not provide effective and durable protection, either due to waning immunity or due to poor antibody cross-reactivity to new variants. Typically, T cells recognize conserved nonmutable viral epitopes and development of T cell–based vaccines might provide broad immunity to SARS-CoV-2 variants. In this study, we show that adjuvanted spike protein–based experimental vaccines elicited potent respiratory or systemic CD4 and CD8 T cell memory and protected against SARS-CoV-2, in the absence of virus-neutralizing antibodies. Thus, development of T cell–based vaccines might be key to protect against antibody-escape SARS-CoV-2 variants that can potentially overcome immunity induced by current vaccines.

CD8+ cytotoxic T lymphocytes (CTLs) are critical for clearing many viral infections, and protective CTL memory can be induced by vaccination with attenuated viruses and vectors. Non-replicating vaccines are typically potentiated by the addition of adjuvants that enhance humoral responses, however few are capable of generating CTL responses. Adjuplex is a carbomer-lecithin-based adjuvant demonstrated to elicit robust humoral immunity to non-replicating antigens. We report that mice immunized with non-replicating Adjuplex-adjuvanted vaccines generated robust antigen-specific CTL responses. Vaccination by the subcutaneous or the intranasal route stimulated systemic and mucosal CTL memory respectively. However, only CTL memory induced by intranasal vaccination was protective against influenza viral challenge, and correlated with an enhancement of memory CTLs in the airways and CD103+ CD69+ CXCR3+ resident memory-like CTLs in the lungs. Mechanistically, Myd88-deficient mice mounted primary CTL responses to Adjuplex vaccines that were similar in magnitude to wild-type mice, but exhibited altered differentiation of effector cell subsets. Immune potentiating effects of Adjuplex entailed alterations in the frequency of antigen-presenting-cell subsets in vaccine draining lymph nodes, and in the lungs and airways following intranasal vaccination. Further, Adjuplex enhanced the ability of dendritic cells to promote antigen-induced proliferation of naïve CD8 T cells by modulating antigen uptake, its intracellular localization, and rate of processing. Taken together, we have identified an adjuvant that elicits both systemic and mucosal CTL memory to non-replicating antigens, and engenders protective CTL-based heterosubtypic immunity to influenza A virus in the respiratory tract. Further, findings presented in this manuscript have provided key insights into the mechanisms and factors that govern the induction and programming of systemic and protective memory CTLs in the respiratory tract.

A private zoological facility experienced an outbreak of malignant catarrhal fever (MCF) in 3 bongo antelope (Tragelaphus eurycerus). All cases were periparturient bongos that presented acutely anorectic beginning ~6 weeks after being housed with a Nubian ibex. Disease quickly progressed to respiratory distress and death within 24-72 hours of onset of clinical signs. Consistent gross findings in affected bongos were pulmonary edema and small pale tan foci in the livers. Histological lesions included a nonsuppurative vasculitis in multiple tissues, which is well recognized in MCF, but additionally included necrotizing cholangiohepatitis and neutrophilic, necrotizing myocarditis. Ibex-associated viral DNA was detected by polymerase chain reaction and was identical in sequence whether derived from bongos or ibex. The sequence closely matched an MCF viral DNA fragment that had been amplified from an ibex and bongo in a previous case report.