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Weiss and colleagues identify a role for the endoplasmic reticulum-tethered PI transfer protein Nir3 in replenishing plasma membrane PIP2 levels in DN3-DP thymocytes, thereby increasing the sensitivity of developing thymocytes to weak TCR agonists.
Boussiotis and colleagues show that the tyrosine phosphatase SHP-2 regulates the differentiation and antitumor function of monocytes downstream of the inhibitory PD-1 receptor.
Ha and colleagues show that loss of PD-1 expression on regulatory T cells in the tumor environment reduces their metabolic fitness and proliferative capacity.
The regulatory protein SREBP is required for CD8+ T cell metabolic reprogramming after activation. Luo et al. demonstrate that stimulated B cells require SCAP, a regulator of SREBP, for metabolic reprogramming and the formation and maintenance of germinal center B cells.
Stepanek and colleagues demonstrate that the LCK kinase associated with CD4 or CD8 co-receptors has kinase-dependent and kinase-independent roles in T cell activation.
De Jong and colleagues identify staphylococcal phosphatidylglycerol lipids as antigens for human CD1a-restricted T cells, which promote type 2 immune responses and may contribute to atopic dermatitis.
Gata3 upregulation is required for TH2 cell polarization. McKenzie and colleagues find that integrin αvβ3 is upregulated by Gata3 and that this is crucial in inducing FAK–mTOR signaling required for TH2 cell differentiation.
Exhausted CD8+ T cells with diminished effector functions accumulate in tumors. Here, the authors show that hypoxia induces a suppressive phenotype in exhausted T cells and that interfering with hypoxia-mediated CD39 expression limits immunosuppression in the tumor and augments immunotherapy, resulting in arrest of tumor growth.
Cancer immunotherapies can be limited by terminally dysfunctional T cells in the tumor microenvironment. Here the authors present a model of stable human T cell dysfunction to show that TGFβ contributes to this terminal dysfunction which can be therapeutically inhibited by simultaneously blocking TGFβ1 and boosting bone morphogenetic protein (BMP) signaling.
The factors controlling monocyte fate commitment toward macrophages versus dendritic cells are unclear. Here the authors show that ETV3 and ETV6 enable dendritic cell differentiation by repressing the macrophage transcriptional program.
Manthiram and colleagues analyze the peripheral blood, tonsils and adenoids in children undergoing tonsillectomy or adenoidectomy and find evidence of continued tissue-specific immunity to SARS-CoV-2 and viral RNA persistence weeks to months after acute infection.
Modeling a rare bone marrow failure disorder due to haploinsufficiency for the MECOM transcription factor identifies a human hematopoietic stem cell regulatory network, which is co-opted by high-risk leukemias.
Goronzy and colleagues examine differences in naive CD4+ T cells from young and older adults to TCR stimulation. They find reduced HELIOS expression in the elderly, resulting in increased CD25 expression and activation of pSTAT5 in FOXP3− T cells. This scenario favors generation of short-lived effector T cells over memory cell populations.
Ammonia detoxification is generally thought to occur exclusively in the liver. Here the authors show that ammonia detoxification via the urea and citrulline cycles is utilized by memory CD8+ T cells to maintain the longevity.
Haimon et al. examine the function of microglia in a relapsing–remitting mouse model of multiple sclerosis, finding that these cells preferentially interact with regulatory T cells compared with effector T cells, and that these cognate interactions require interferon-γ signaling and are critical to maintain regulatory T cell activity.
Based on the identification of CD4+ T cell clones specific for distinct epitopes in the SARS-CoV-2 proteins, Long and colleagues characterize how mutations in these epitopes lead to loss of recognition by the CD4+ T cells elicited by natural infection or vaccination.
Parenteral BCG vaccination has been shown to drive innate immune memory responses that can affect the response to pathogens other than mycobacteria. Here the authors show an innate immune memory mechanism whereby subcutaneous BCG vaccination alters the intestinal microbiome and in turn can train alveolar macrophages in the lungs.
Gringhuis and colleagues show that the extent of type I IFN responses induced by fungal stimulation in human DCs modulate the activation of TGF-β and the production of pathogenic or non-pathogenic TH17 cells.
A dogma in the inflammasome field is that NLRP3 activation occurs at dispersed vesicles of the trans-Golgi network. Here, Ricci and colleagues find that these vesicles are of endosomal origin and that endosomes comprise the compartment where NLRP3 is activated.
Yang and colleagues report that MAIT cells are present in the meninges where they play an essential role in repressing tissue ROS accumulation and preserving meningeal barrier integrity.