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Tuoqi Wu and colleagues show that the transcriptional repressor BACH2 is required early after chronic viral infection to enforce a stem-like fate in activated CD8+ T cells. BACH2 acts to suppress genes that lead to the exhausted cell state.
Glioblastoma is one of the most intractable tumors and presents a hypoxic and immunologically cold microenvironment. Lee and colleagues demonstrate that normalizing oxygen tension unleashes γδ T cell anti-glioblastoma function.
Severe COVID-19 is characterized by hyperinflammation, and there is a need for accurate predictive biomarkers of progression. Lehuen et al. demonstrate that patients with severe COVID-19 show a dramatic loss of MAIT cells, and those that do remain are in a highly activated state.
Fessler and colleagues report that loss of the IFN-γ-induced GTPase IRGM1 results in autoinflammatory disease. Deficient IRGM1 activity led to defective lysosomal maturation and impaired mitophagy, prompting the release of cytosolic mtDNA and thereby activating the cGAS–STING pathway.
The microbiome can affect susceptibility to developing asthma. Marsland and colleagues show that changes in the microbial population lead to enrichment of an l-tyrosine metabolite, p-cresol sulfate, which can protect mice against allergic inflammation.
γδ T cells have potent effector functions through their production of IFN-γ or IL-17. Pennington and colleagues demonstrate that IFN-γ+ γδ T and IL-17+ γδ T cells have distinct metabolic requirements that can be independently targeted to elicit specific immune responses.
Helper T cell subsets are characterized functionally by the cytokines they produce. Benoist and colleagues demonstrate that in vivo helper T cells do not manifest as discrete helper subsets but rather form a continuum shaped by microbial exposure.
McKenzie and colleagues show RORα expression in early thymic progenitors overrides BCL11B-dependent suppression of Id2 and Nfil3 expression. In turn, ID2 suppresses the activity of the E proteins that are required for T lineage development, thereby promoting ILC2 cell generation in the thymus.
IL-2 is a classic T cell growth factor. Huang and colleagues demonstrate, however, that chronic IL-2 stimulation leads to a new exhaustion pathway that impairs antitumor immune responses.
Melnick and colleagues show that the cohesin complex exhibits dose-dependent regulation of chromatin remodeling that accompanies the transition of germinal center B cells to plasma cells, which is necessary to prevent lymphomagenesis.
Junqueira et al. show that human γδ T cells control erythrocytic Plasmodium falciparum infection by multiple mechanisms: antibody-dependent phagocytosis, cytotoxic-granule-mediated erythrocyte lysis and direct parasite killing.
CHAPLE disease is a lethal syndrome caused by genetic loss of the complement regulatory protein CD55. Lenardo, Ozen and their colleagues report that blockade of C5 complement activation in a small cohort of pediatric patients with CHAPLE disease reduced gastrointestinal pathology and restored their immunity and growth.
Thimme and colleagues identify a molecular signature of T cell exhaustion resembling a ‘chronic scar’ that is imprinted in hepatitis C virus–specific CD8+ T cells and cannot simply be reversed by viral clearance.
Metabolic rewiring of cytotoxic T lymphocytes (CTLs) can impair their antitumor functions. Sun and colleagues demonstrate that CTL-intrinsic activity of the kinase NIK is essential for CTL metabolic fitness in the tumor microenvironment.
Delgoffe and colleagues show that continuous TCR signaling and hypoxia increase Blimp-1, which suppresses PGC-1α-dependent mitochondrial reprogramming and increases reactive oxygen species generation. Such conditions promote T cell exhaustion.
Damage-associated molecular patterns (DAMPs) are released during necrotic cell death and contribute to driving inflammation. Rathinam and colleagues show that galectin-1 is a new DAMP that functions by inhibiting the receptor phosphatase CD45.