While the start of the new year is filled with the promise of the year to come, it is also a fine time to reflect on achievements from the previous year. To this end, the editorial team of Immunology & Cell Biology (ICB) has selected the top research articles accepted between 1 July 2020 and 30 June 2021, and these articles have been compiled here in our first Virtual Issue for 2022. If you look closely, you will notice that 11 and not 10 articles have been selected; 2021 was a good year. With this Virtual Issue, we are proud to showcase the high quality and breadth of immunological research published in ICB.

ICB's top research articles from 1 July 2020 to 30 June 2021 (in order of publication date): Guillerey et al.1 Systemic administration of IL-33 induces a population of circulating KLRG1hi type 2 innate lymphoid cells and inhibits type 1 innate immunity against multiple myeloma. Schröder et al.2 Impact of salt and the osmoprotective transcription factor NFAT-5 on macrophages during mechanical strain. Feng et al.3 Vagal-α7nAChR signaling attenuates allergic asthma responses and facilitates asthma tolerance by regulating inflammatory group 2 innate lymphoid cells. Cai et al.4 ROR agonist hampers the proliferation and survival of postactivated CD8+ T cells through the downregulation of cholesterol synthesis-related genes. Crosse et al.5 Viperin binds STING and enhances the type-1 interferon response following dsDNA detection. Tang et al.6 Bcl-3 suppresses differentiation of RORγt+ regulatory T cells. Chambers et al.7 Nitric oxide inhibits interleukin-1-mediated protection against Escherichia coli K1-induced sepsis and meningitis in a neonatal murine model. Patchett et al.8 Mesenchymal plasticity of devil facial tumor cells during in vivo vaccine and immunotherapy trials. Bello et al.9 Impact of Chk1 dosage on somatic hypermutation in vivo. Hewavisenti et al.10 Tissue-resident regulatory T cells accumulate at human barrier lymphoid organs. Rowntree et al.11 SARS-CoV-2-specific CD8+ T-cell responses and TCR signatures in the context of a prominent HLA-A*24:02 allomorph.

We start our Virtual Issue with a study by Patchett et al.8 investigating how devil facial tumor (DFT) cells respond to a changing host environment. Using DFT1 cells to challenge immunized and unimmunized devils, the investigators compared the transcriptomic profile of the tumors that developed. The strength of this study lies in the analysis of multiple tumors per animal and the assessment of changes over time in each tumor. This approach provides unique insight into the ability of the DFT1 tumors to respond to different host environments including prophylactic immunization and immunotherapy and revealed the ability of DFT1 tumors to respond to immune pressure by dedifferentiation, thus escaping immune clearance. It also contributes fundamental information as to how a single transmissible tumor can establish and escape immune control in genetically distinct individuals.

Guillerey et al.1 continue the focus on cancer but shift to investigate type 2 innate lymphoid cells (ILC2) in multiple myeloma, a plasma-cell malignancy. Looking in the bone marrow niche where this cancer develops, they identified alterations in the phenotype and function of the local ILC2 population. Investigating this population further, they found that the administration of interleukin (IL)-33, which has been shown to promote type 1 immunity, instead enhanced a population of circulating ILC2 that directly inhibited the anti-tumor action of IL-12 and IL-18. This study reveals an unanticipated and unwanted consequence of IL-33 during multiple myeloma that argues against the use of IL-33 as a therapy in this situation. Another of our top research articles also centered on the in vivo function of ILC2 but in asthma, not cancer. While ILC2 are known to be detrimental in asthma, Feng et al.3 took a novel approach and asked whether their involvement was regulated by neuroimmune signals from the vagus nerve. In particular, these authors investigated how signaling through the α7 nicotinic acetylcholine receptor influenced the development of asthma and asthma tolerance induced by allergen feeding. Interestingly, they found that interrupting the vagal circuit by vagotomy or pulmonary C-fibre degeneration reduced allergic asthma while deficiency in the α7 nicotinic acetylcholine receptor led to a significantly more severe disease characterized by increased ILC2 presence in the lung. This study underscores the importance of neuroimmune signaling in regulating inflammation – both positively and negatively.

Studies on T-cell phenotypes and functions are again well represented in our top research articles. This Virtual Issue features three studies that delve into how tissue residency, RORγt, Bcl-3 and cholesterol affect regulatory (Treg) and CD8+ T-cell location and function. Using human tissues to explore tissue-resident Treg, Hewavisenti et al.10 compared the phenotype and function of Treg in tonsils and spleens during homeostasis and discovered that these cells are located principally at the B-cell:T-cell border and share features with T follicular helper cells. Given that NFκB signaling increases FoxP3+ cells, Tang et al.6 studied how the atypical IκB family member, Bcl-3, regulates Treg populations in mice. Their work revealed a novel role for Bcl-3 in supressing the development of RORγt+ Treg, and, when absent (i.e. Bcl-3-deficiency), the increase in RORγt+ Treg was correlated with a decrease in dextran sulfate sodium-induced colitis. The third article in this group examined the effect of activating retinoic acid receptor-related orphan receptors (ROR) such as RORγ on post-activated CD8+ T cells.4 Using selective ROR agonists, Cai et al. uncovered an unexpected role for ROR in attenuating CD8+ T-cell responses by downregulating cholesterol synthesis. Moreover, this regulation of CD8+ T-cell proliferation and survival could be rescued by cholesterol supplementation, highlighting the importance of energy regulation in immunity.

Studies by Rowntree et al.11 and Bello et al.9 delve into the world of antigen receptors to characterize the TCR signatures in COVID-19-convalescent and healthy HLA-A*24:02+ individuals and to determine how the checkpoint protein Chk1 influences antibody diversification during somatic hypermutation. Because HLA shapes the T-cell repertoire during development, and the HLA-A*24:02 allomorph is one of the most frequent HLA class 1 molecules in Indigenous and Asian populations, this study has particular relevance for Australia and New Zealand, as it begins to describe the relevant SARS-CoV-2 epitopes and TCRαβ repertoire in this high risk group. In contrast to the TCR, the ability of the BCR to diversify after activation via somatic hypermutation is the subject of the study by Bello et al. Because somatic hypermutation is a process of continuous DNA damage, B cells must circumvent checkpoint responses and evade apoptosis to survive and diversify. As it turns out, the genetic dosage of Chk1 is important in supporting B-cell survival during somatic hypermutation as Chk1 heterozygosity led to reduced mutations and reduced antibody diversity. An interesting twist to the story is that the authors found the decrease in mutations to be preferentially at C:G and not A:T pairs, suggesting that the factors regulating these mutations may be different.

The final three top research articles enhance our understanding of innate immune responses during infection and during non-infectious activation. Crosse et al.5 analyzed viperin’s anti-viral activity to understand why it has such broad anti-viral activity. A detailed and elegant dissection of viperin's responses to double-stranded DNA revealed that viperin has dual activity and can enhance innate responses to DNA viruses via STING independently of its radical SAM enzyme activity. Shifting to bacterial meningitis in neonates, Chambers et al.7 investigated another important component of innate immunity – nitric oxide (NO). Because IL-1 signaling has been shown to be protective in adults infected with neonatal-associated Escherichia coli (NMEC), the investigators studied its role in neonates. They uncovered a new role for NO in suppressing IL-1 production and thus inhibiting the protective actions of IL-1 signaling in controlling NMEC infection in neonatal mice. This enhanced NO response may reveal a more general mechanism by which neonates innately respond to infections. Our final article in this Virtual Issue examined how salt and mechanical strain (tensile or compressive), which models orthodontic tooth movement, can influence macrophage gene expression and function.2 In this in vitro study, Schröder et al. found that compressive and tensile strains had distinct effects, with the compressive strain leading to greater enhancement in proinflammatory responses including TNFα, IL-6 and NFAT-5. The addition of salt to this model further enhanced selected pro-inflammatory signals upregulated by mechanical strain, suggesting that this environment may contribute to dental root resorption or periodontal bone loss.

Together, the articles in this Virtual Issue highlight not only the ever-increasing role of immune cells in health and disease but also the breadth and depth of immunological research published in ICB each year. Therefore, I invite you to continue to expand our immunological horizons and publish your exciting new research in ICB. Finally, I would like to thank all our authors, who have trusted ICB with their research as well as the ICB editorial team, board members and reviewers who have donated their time and expertise to ICB over the past year.