Reviews & Analysis

Wherry and colleagues describe how anti-PD-1 immunotherapy impacts outcomes of influenza vaccination in patients with cancer, and specifically, how it increases seroconversion and affects quantitative and qualitative aspects of antibodies and follicular T helper cell responses.

Multistep mechanosensing of lymphocyte infiltration and proliferation by the remodeling stroma and matrix underlies the immensely rapid and massive tissue expansion by lymph nodes in response to immune challenge.

Deacetylation of specific lysine residues in the DNA-binding domain of the transcription factors IRF3 and IRF7 by SIRT1 is necessary for liquid–liquid phase separation and transactivation of type I interferons. SIRT1 agonists partially restored the impaired innate immune responses in senescent cells and aged mice, suggestive of a possible strategy for preventing innate immunosenescence.

The response of circulating effector CD4 T cells to type I interferons (IFN-I) correlates with the overall survival of patients with cancer receiving immune checkpoint inhibition. IFN-I responsiveness is already epigenetically encoded before treatment initiation, highlighting a deterministic, clinically relevant feature that can predict therapeutic efficacy.

Boussiotis and colleagues review the hallmarks of tumor-associated macrophages and discuss the mechanisms that contribute to their pathophysiological adaptations to the tumor microenvironment.

Specific brain circuits recruited during stress contribute to differential immune responses and affect how the immune system handles viral and autoimmune challenges.

Immune checkpoint blocking therapies do not always work and come with some risks, but identifying non-responders and patients at risk of adverse events is becoming easier and more accurate.

Yu et al. review the roles played by follicular helper T cells in sustaining germinal center B cell responses and vaccination strategies, as well as potential pathogenic autoimmune responses.

In airway epithelial cells, exposure to allergen proteases induces the stress granules-mediated transfer of IL-33 from the nucleus to the cytoplasm and extracellular release through gasdermin D pores containing a newly described active fragment.

Crystal structures of the immune checkpoint protein LAG3 reveal critical binding interfaces for inhibitory antibodies and cellular ligands, such as FGL1 and MHC class II molecules. These structures provide insight into the dimeric assembly of LAG3 proteins on the surface of T cells and suggest FGL1-induced clustering as an immunomodulatory mechanism.

A single-cell sequencing study shows that the human memory B cell repertoire is dominated by large IgM, IgG2 and IgA immunoglobulin families, whereas IgG1 families, including those specific for recall antigens, are of a small size. Multi-year analysis shows that memory B cell families are highly stable and that plasmablasts of T cell–independent and T cell–dependent isotypes are produced in a recurrent manner.

Extrathymic MHCII⁺Rorc⁺ Aire-expressing cells that share characteristics with type 3 innate lymphoid cells (ILC3s) internalize C. albicans and present its antigens, priming the development of Candida-specific T_H17 cells.

Lymphocyte activation gene 3 (LAG3) is an important checkpoint inhibitor molecule of immunotherapeutic interest. New crystal structures of LAG3 provide important insight into its molecular architecture, laying the groundwork for future basic and applied investigations.

Qi et al. provide an in-depth analysis of antibody responses generated in response to SARS-CoV-2.

Instructed by locally increased levels of glucocorticoids in the skin after acute hair loss, regulatory T cells communicate with hair follicle stem cells by producing TGFβ3 to stimulate stem-cell proliferation and hair regrowth.

Using high-resolution molecular and optical mapping of the three-dimensional genome, we found that the transcription factor TCF-1 is linked to changes in the structure of topologically associating domains in T cell progenitors that lead to interactions between previously insulated regulatory elements and target genes at late stages of T cell development.

Regulatory T cells that express high levels of IL-1R and ICOS display transcriptional features of antigen specificity, are highly suppressive and distinguish tumors from non-malignant inflamed tissues

Inflamed tissue has a special milieu, with hypoxia, high levels of metabolites from anaerobic glycolysis, and acidosis. Stimulation of a proton-activated receptor, TDAG8 (GPR65), in T cells has an important role in inflammatory bowel disease by balancing pro- and anti-inflammatory signals.

This study shows that systemic hypoxia alters the response of the bone marrow to inflammation by reducing type I interferon signaling and suppressing the accumulation of monocyte-derived macrophages in the lung. These events, in turn, hinder the resolution of lung inflammation.

Broadly protective antibodies to SARS-CoV-2 inform vaccine improvements and are directly used for treatment and prevention. New technologies are enabling the recovery of thousands of antibody examples, and workflows to rapidly identify the most potent examples are accelerating discovery.