Research articles

Adipose tissue-resident regulatory T (T_reg) cells are important for maintaining normal metabolic function and adiposity. Li and colleagues demonstrate that insulin signaling directly controls adipose T_reg cell development and functionality

Regulatory T cells are functional in a broad-spectrum systemic autoimmune disease and are capable of suppressing innate and adaptive immune responses, reversing established tissue inflammation and enabling long-term restoration of immunological health.

Tissue-resident memory T (T_RM) cells are distributed throughout the body as relatively sessile populations. Mackay and colleagues find that the tissue in which T_RM cells are generated dictates their properties and is in turn defined according to T_RM-cell-intrinsic sensitivity to signaling via the cytokine TGFβ.

The beta variant (B.1.351) is to date the most resistant to neutralization of the SARS-CoV-2 variants. Using nonhuman primates, Seder and colleagues demonstrate that double vaccination with a high dose of the lipid nanoparticle vaccine mRNA-1273 protects against infection with the beta variant.

T follicular helper (T_FH) cells are important for the generation of effective antibody responses. Yu and colleagues find that T_FH cells are exceptionally sensitive to death by ferroptosis and that this process is regulated by the activity of the selenoenzyme GPX4.

Khazaie and colleagues show that TCF-1 cooperates with FOXP3 to differentially regulate independent suppressive activities of T_reg cells. T_reg cell–specific deficiency of TCF-1 increases tumor load in mice predisposed to polyposis. Functionally, TCF-1-deficient T_reg cells suppress viral antigen–specific CD8⁺ T cell cytotoxicity, but TCF-1-deficient T_reg cells fail to suppress T_H1 or T_H17 polarization of conventional CD4⁺ T cells. This scenario leads to increased cytokine-mediated tissue inflammation but still restrains the adaptive antitumor cytotoxicity.

Zhang and colleagues identify a role for cell death by glutathione peroxidase 4 (GPX4)-regulated ferroptosis in neutrophils from patients with systemic lupus erythematosus, which is triggered by type I interferons and autoreactive antibodies and contributes to lupus pathogenesis. Inhibiting accumulation of oxidative mediators by GPX4 suppresses ferroptosis.

Lucas and colleagues describe loss-of-function variants in the X-linked ETS transcription factor ELF4 in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD)-like features.

Wherry and colleagues examine whether exhausted T cells (T_EX) can differentiate into functional memory T cells (T_MEM) when chronic antigen is withdrawn. Using the chronic LCMV infection mouse model, they show that ‘recovering’ T_EX cells (REC-T_EX) only partially recover immunophenotypic and functional characteristics of T_MEM cells. The epigenomic status of REC-T_EX cells more closely resembles that of T_EX cells, and, upon rechallenge, the REC-T_EX cells were still compromised in their ability to respond to virus.

Lauer and colleagues examine CD8⁺ T cells following cure of human hepatitis C virus (HCV) infection. CD8⁺ T cells exposed to chronic HCV-specific activation show durable functional, phenotypic and transcriptional exhaustion that is maintained even after antigen stimulus is removed.

The transcription factor ThPOK is critical for homeostasis and differentiation of mature helper T cells. Here, Kappes and colleagues describe a ThPOK-mediated positive autoregulatory loop that is crucial for tissue-specific T_reg cell differentiation, maintenance of intestinal T_reg cell integrity and conversion of these cells into CD4⁺ intraepithelial lymphocytes.

The degree of plasticity in the epigenetic landscape of exhausted T cells has been unclear. Sen and colleagues find that exhausted CD8⁺ T cells demonstrate a stable core epigenetic exhaustion signature that persists independent of inflammation or viral antigen.

Neutrophils demonstrate highly dynamic functional and transcriptional changes depending on their tissue environment. Udalova and colleagues use an inflammation model to examine neutrophils and find that the transcription factors RUNX1 and KLF6 control maturation; RELB, IRF5 and JUNB drive effector responses; and RFX2 and RELB promote survival.

Chronic antigen stimulation leads to CD8⁺ T cell exhaustion, which is mediated by persistent activation of the transcription factor NFAT in the absence of AP-1. Seo, González-Avalos and colleagues show that overexpressed BATF cooperates with IRF4 to counteract NFAT-induced exhaustion and promote better tumor control by CAR T cells in mouse models.

Distinct subsets of effector CD8⁺ T cells can arise in chronically infected mice. Cui and colleagues examine the epigenetic trajectory of TCF-1⁺Ly108⁺ ‘stem-like’ progenitor cells differentiating into CX₃CR1⁺ cytolytic effector CD8⁺ T cells in LCMV-infected mice. Single-cell transcriptomic and ATAC-seq analyses reveal that this progression requires the transcription factors T-bet and BATF.

Antibody-dependent enhancement (ADE) is an important safety concern for vaccine development against dengue virus (DENV) and the antigenically related Zika virus (ZIKV). Gao and colleagues designed a ZIKV vaccine that induced sterilizing immunity and fetal protection in mice challenged with ZIKV and did not induce ADE following subsequent DENV infection.

Ludewig and colleagues show that adenovirus immunization fosters the formation of pulmonary immune-stimulating niches underpinned by fibroblastic stromal cells that maintain ‘inflating’ memory CD8⁺ T cells through the provision of interleukin-33.

Cell death in the context of cancer therapies is often associated with immunogenicity. Taniguchi and colleagues instead find that release of the cellular protein TCTP following cell death triggers an immunosuppressive pathway in the tumor microenvironment.

Modlin and colleagues examined the skin lesions of human leprosy patients using single-cell RNA sequencing coupled to cellular spatial mapping. Their analysis maps the architecture of granulomas in leprosy lesions from patients with leprosy with localized disease (tuberculoid leprosy, reversal reaction) to those with progressive infection (lepromatous leprosy).

Vijayanand and colleagues show highly suppressive CD4⁺CTLA-4⁺PD-1⁺ follicular regulatory T (T_FR) cells reside within tumor microenvironments. Depleting T_FR cells or blocking their activity with CTLA-4-depleting antibodies before anti-PD-1 checkpoint blockade therapy improved the efficacy of anti-PD-1 treatment in mouse tumor models and was also associated with better survival outcomes in a large cohort of patients with melanoma.