The evolutionary conservation of the catalytically inactive α-tryptase gene has remained a mystery. In this issue of JEM, Le et al. unveil the existence of a novel but natural tryptase, heteromeric α/β-tryptase, a critical mediator of α-tryptase–associated diseases.
Brief Definitive Reports
ILC3s integrate glycolysis and mitochondrial production of reactive oxygen species to fulfill activation demands
ILC3s are innate immune cells in the intestine that contribute to mucosal barrier integrity and support antimicrobial responses. Di Luccia et al. show that an mTORC1-HIF1α–mediated metabolic program sustains ILC3 numbers and activation in both mouse and human.
Denton et al. show that stromal cells of the adult LN derive from a common embryonic FAP+ progenitor present when the LN first forms. FAP+ progenitors differentiate locally to form the LN stromal network and also become tertiary lymphoid structure stromal cells in nonlymphoid tissues.
Technical Advances and Resources
Combination of quadruplex qPCR and next-generation sequencing for qualitative and quantitative analysis of the HIV-1 latent reservoir
HIV-1 cure research seeks to decrease or eliminate the latent reservoir. The evaluation of such curative strategies requires accurate measures of the reservoir. Gaebler et al. describe a combined multicolor qPCR and next-generation sequencing method that enables the sensitive and specific characterization of the HIV-1 latent reservoir.
Microglia are a heterogeneous population whose identity and function are dictated by signals from their microenvironment. Kana et al. show CSF-1 signaling is critical for cerebellar microglial transcriptional identity and homeostasis, and that altering the CSF-1–CSF-1R axis leads to motor and behavioral defects.
The authors generate and characterize a panel of highly neutralizing antibodies against Mayaro virus, an emerging alphavirus. They find that neutralization activity alone is not sufficient for antibodies to protect mice from disease and that Fc effector functions also are required.
ZIKV infection during pregnancy causes microcephaly, but not all neonates are affected. This study shows that features of the maternal antibodies correlate with the risk of ZIKV-associated microcephaly.
We developed an anti-idiotypic antibody that specifically engages target B cells while mitigating off-target responses. This approach can be used as a vaccine strategy for variable pathogens where specific precursor B cells have been identified to correlate with protection.
Detection and activation of HIV broadly neutralizing antibody precursor B cells using anti-idiotypes
An anti-idiotype recognizing the germline version of a broadly neutralizing antibody was utilized to identify human B cells expressing similar germline antibodies and was converted to an immunogen to stimulate transgenic murine B cells in vivo despite the presence of anergy.
Impact of naturally forming human α/β-tryptase heterotetramers in the pathogenesis of hereditary α-tryptasemia
Human α/β-tryptase heterotetramer, a previously hidden form of tryptase, explains some of the unusual clinical features of hereditary α-tryptasemia. α/β-Tryptase forms naturally in mast cells and, when secreted, activates clinically relevant proteins, likely impacting a variety of mast cell disorders.
Martin et al. demonstrate that CD97 is a critical regulator of leukemia stem cell (LSC) function. CD97 is overexpressed in the vast majority of AML patients and promotes AML blast growth, survival, and differentiation. Collectively, these data credential CD97 as a novel and promising therapeutic target in AML.
Editing of the gut microbiota reduces carcinogenesis in mouse models of colitis-associated colorectal cancer
Enterobacteriaceae family members such as E. coli exacerbate development of intestinal malignancy. Zhu et al. report that targeting the metabolism of protumoral Enterobacteriaceae by tungstate prevents tumor development in murine models of colitis-associated colorectal cancer.
Specific targeting of CD163+ TAMs mobilizes inflammatory monocytes and promotes T cell–mediated tumor regression
Etzerodt et al. show that the specific targeting of CD163+ macrophages in melanoma drives inflammatory monocyte influx and promotes antitumor immunity, illustrating the importance of selective targeting of tumor-associated myeloid cells for achieving optimal therapeutic responses.
Bartolomé-Casado et al. demonstrate that human gut contains large numbers of resident memory CD8 T cells that survive for years. Intestinal CD8 Trm cells have a clonally expanded immune repertoire that is stable over time and exhibit enhanced protective capabilities.
RRAS2 is involved in setting the threshold for negative selection of T cells in the thymus. In its absence, most autoreactive T cells are eliminated, and, consequently, mice become resistant to development of autoimmune diseases in experimental models.