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Innate lymphoid cells (ILCs) are resident in the lung and are involved in both the maintenance of homeostasis and the pathogenesis of respiratory diseases. In this study, murine lung ILCs were characterized using flow cytometry and the impact of mouse age, sex and strain were assessed. Lung ILCs were found as early as postnatal day 4 and numbers peaked at 2 weeks, and then decreased as the lung matured. During postnatal lung development, ILC expressed differential amounts of group 2 ILC (ILC2)-associated cell surface antigens including ST2, CD90.2 and ICOS. Using Il5venus Il13td-tomato dual reporter mice, neonates were found to have increased constitutive interleukin (IL)-13 expression compared with adult mice. Neonates and adults had similar ratios of IL-5+ CD45+ leukocytes; however, these cells were mostly composed of ILCs in neonates and T cells in adults. Sex-specific differences in ILC numbers were also observed, with females having greater numbers of lung ILCs than males in both neonatal and adult mice. Female lung ILCs also expressed higher levels of ICOS and decreased KLRG1. Mouse strain also impacted on lung ILCs with BALB/c mice having more ILCs in the lung and increased expression of ST2 and ICOS compared with C57BL/6J mice. Collectively, these data show that lung ILC numbers, cell surface antigen expression, IL-5 and IL-13 levels differed between neonatal and adult lung ILCs. In addition, cell surface antigens commonly used for ILC2 quantification, such as ST2, CD90.2 and ICOS, differ depending on age, sex and strain and these are important considerations for consistent universal identification of lung ILC2s.

Type 2 innate lymphoid cells (ILC2s) are important producers of type 2 cytokines whose role in hematological cancers remains unclear. ILC2s are a heterogenous population encompassing distinct subsets with different tissue localization and cytokine responsiveness. In this study, we investigated the role of bone marrow (BM) ILC2s and IL‐33‐stimulated ILC2s in multiple myeloma, a plasma cell malignancy that develops in the BM. We found that myeloma growth was associated with phenotypic and functional alterations of BM ILC2s, characterized by an increased expression of maturation markers and reduced cytokine response to IL‐2/IL‐33. We identified a population of KLRG1hi ILC2s that preferentially accumulated in the liver and spleen of Il2rg‐/‐ Rag2‐/‐ mice reconstituted with BM ILC2s. A similar population of KLRG1hi ILC2s was observed in the blood, liver and spleen of IL‐33‐treated wild‐type mice. The presence of KLRG1hi ILC2s in ILC2‐reconstituted Il2rg‐/‐ Rag2‐/‐ mice or in IL‐33‐treated wild‐type mice was associated with increased eosinophil numbers but had no effect on myeloma progression. Interestingly, while decreased myeloma growth was observed following treatment of Rag‐deficient mice with the type 1 cytokines IL‐12 and IL‐18, this protection was reversed when mice received a combined treatment of IL‐33 together with IL‐12 and IL‐18. In summary, our data indicate that IL‐33 treatment induces a population of circulating inflammatory KLRG1hi ILC2s and inhibits type 1 immunity against multiple myeloma. These results argue against therapeutic administration of IL‐33 to myeloma patients.

Vaccination against γ-herpesviruses has proved difficult. CD4+ T cells are essential to contain infection, but how best to prime them and whether this can reduce viral loads remain unclear. To address these questions, we used ovalbumin (OVA) as a model antigen, delivering it with murine cytomegalovirus (MCMV) to protect mice against OVA-expressing murine herpesvirus-4 (MuHV-4). Membrane-associated OVA (mOVA) was more effective than soluble OVA, both to prime CD4+ T cells and as an effector target. It was also a better target than an OVA epitope limited to infected cells, suggesting that protective CD4+ T cells recognize infected cell debris rather than infected cells themselves. While MCMV-mOVA protected acutely against MuHV-4-mOVA, long-term protection was incomplete, even when OVA-specific CD8+ T cells and B cells were also primed. Thus, even optimized single-target vaccines may poorly reduce long-term γ-herpesvirus infections.

FOXP3+ regulatory T (Treg) cells are essential for immunological tolerance and immune homeostasis. Despite a great deal of interest in modulating their number and function for the treatment of autoimmune disease or cancer, the precise mechanisms that control the homeostasis of Treg cells remain unclear. We report a new ENU-induced mutant mouse, lack of costimulation (loco), with atopic dermatitis and Treg cell deficiency typical of Card11 loss-of-function mutants. Three distinct single nucleotide variants were found in the Card11 introns 2, 10 and 20 that cause the loss of CARD11 expression in these mutant mice. These mutations caused the loss of thymic-derived, Neuropilin-1+ (NRP1+ ) Treg cells in neonatal and adult loco mice; however, residual peripherally induced NRP1- Treg cells remained. These peripherally generated Treg cells could be expanded in vivo by the administration of IL-2:anti-IL-2 complexes, indicating that this key homeostatic signaling axis remained intact in CARD11-deficient Treg cells. Furthermore, these expanded Treg cells could mediate near-normal suppression of activated, conventional CD4+ T cells, suggesting that CARD11 is dispensable for Treg cell function. In addition to shedding light on the requirements for CARD11 in Treg cell homeostasis and function, these data reveal novel noncoding Card11 loss-of-function mutations that impair the expression of this critical immune-regulatory protein.

BPSM1 (Bone phenotype spontaneous mutant 1) mice develop severe polyarthritis and heart valve disease as a result of a spontaneous mutation in the Tnf gene. In these mice, the insertion of a retrotransposon in the 3' untranslated region of Tnf causes a large increase in the expression of the cytokine. We have found that these mice also develop inducible bronchus‐associated lymphoid tissue (iBALT), as well as nodular lymphoid hyperplasia (NLH) in the bone marrow. Loss of TNFR1 prevents the development of both types of follicles, but deficiency of TNFR1 in the hematopoietic compartment only prevents the iBALT and not the NLH phenotype. We show that the development of arthritis and heart valve disease does not depend on the presence of the tertiary lymphoid tissues. Interestingly, while loss of IL‐17 or IL‐23 limits iBALT and NLH development to some extent, it has no effect on polyarthritis or heart valve disease in BPSM1 mice.

Batf3 is a transcription factor that impacts the development of CD103+ tissue-resident dendritic cells (DCs). However, whether Batf3 is absolutely required for the development of CD8+ DCs remains controversial. Id2 is required for CD8+ DC development. Here we show that bone marrow chimeric mice with a deletion of Id2 in the CD11c compartment lose the ability to reject a skin graft expressing a non-self protein antigen or mount a delayed hypersensitivity response. In contrast, Batf3-/- mice remained competent for skin graft rejection and delayed hypersensitivity, and retained a CD8+ DC population with markers characteristic of the CD11b+ DC lineage, including CD11b, CD4 and CD172α, as well as the key regulator transcription factor IRF4, but lacked IRF8 expression. CD8+ DCs in Batf3-/- mice took up and cleaved protein antigen and larger particles but were unable to phagocytose dying cells, a characteristic feature to the CD8+ DC lineage. These data clarify a requirement for CD8+ lineage DCs to induce effectors of neo-antigen-driven skin graft rejection, and improve our understanding of DC subtype commitment by demonstrating that in the absence of Batf3 CD8+ DCs can change their fate and become CD11b+ DCs.

Suppressor of cytokine signaling (SOCS) proteins are key regulators of innate and adaptive immunity. Mice lacking functional SOCS4 are hypersusceptible to primary infection with influenza A virus (IAV), displaying dysregulated pro-inflammatory cytokine and chemokine production in the lungs, delayed viral clearance and impaired trafficking of influenza-specific CD8(+) T cells to the site of infection. Therefore, we postulated that SOCS4 is a critical regulator of anti-viral immunity. Unexpectedly, SOCS4 was not required for CD8(+) T-cell memory generation, nor was it required to efficiently recall those cells in response to secondary IAV infection. Wild-type or SOCS4-deficient mice primed and re-challenged with serologically different influenza strains, did not show differences in susceptibility to IAV and cleared the virus from the lungs at the same rate. We have not observed differences in trafficking or numbers of IAV-specific cells, numbers of resident memory T cells or in cytokine profiles in lungs of infected animals. Our data show that despite an impaired primary immune response in Socs4(R108X/R108X) mice, SOCS4 is dispensable for an efficient recall response to influenza virus infection.

This report describes advances in the understanding of how we might intervene in destructive processes, such as autoimmunity, infectious disease and cancer, through the development of innovative vaccines and immunotherapeutics.

It is a great pleasure to announce the winners of the Immunology and Cell Biology Publication of the Year Awards. Recipients of the award must be the first authors in one of the following ICB manuscript categories: Original Article, Outstanding Observation, Theoretical Article or Brief Communication. They must also be financial members of the Australasian Society for Immunology Inc. by October of the year in which the article was published. Two awards have been established for outstanding publications. The winner of the Chris and Bhama Parish ICB Publication of the Year Award is awarded a AU$1000 scholarship provided by the Nature Publishing Group and the runner-up is awarded a AU$500 scholarship provided by Thermo Fisher Scientific.

The lung is a fragile network of thin-walled alveoli littered with immune cells that are required to carry out the critical, but normal functions, of gas exchange and antigen sampling. In the adult human, this occurs over the expansive surface area of some 70 m2. The almost constant and direct contact of lung epithelium with the outside environment means that the respiratory tract must maintain a delicate, and tightly regulated balance, to avert almost certain disaster. This is especially true during eradication of a pathogen infection. The fact that lung infection only occasionally goes wrong resulting in a catastrophic outcome suggests that sophisticated mechanisms are in play to keep this process in check.

Sometimes experimental results are highly predictable. Often though, the most important and unanticipated findings in science emerge through creative, insightful and tenacious pursuit of lines of thought that challenge the prevailing dogma.