Arginine Methylation Affects Allergic Asthma See article p. 1525

IL-22 Drives Preterm Labor See article p. 1595

Optimizing Adult Stem Cell Transplant in Humanized Mice See article p. 1652

Unequal P2RX7 Expression Shapes CD8+ T Cell Memory See article p. 1686

HIV Genomic Insertion Leads to Treg-like Cells See article p. 1700

Multiorgan T Cell Analysis in HIV+ Women See article p. 1790

Antitumor Properties of NK Subsets See article p. 1802

NeoScore Model Predicts Neoantigen Immunogenicity See article p. 1813

In this Top Read, Gershater et al. (p. 1595) showed that IL-22 can cause fetal injury and participate in host response to microbial invasion in the amniotic cavity. The authors used a combination of human and murine studies to show that IL-22+ T cells coexpressing RORγt are enriched at the maternal-fetal interface in women with preterm labor and that IL-22 can cross the choriodecidua to the intra-amniotic space. When the authors activated T cells in vivo to initiate preterm birth, they observed a large increase in circulating IL-22 in the amniotic cavity compared with isotype-treated controls. Furthermore, IL-22 administration to the amniotic space shortened the gestation period and led to neonatal death. Finally, the authors showed that IL-22 participates in host defense induced by microbial invasion of the amniotic cavity in both mice and humans, and that the preterm birth caused by infection could be reversed upon IL-22 depletion. These results highlight the dual roles of IL-22 and its impact on late-term pregnancy.

In this Top Read, Christian et al. (p. 1700) demonstrated that the integration of HIV genes into the first exon of BACH2 in primary CD4+ T cells generates T regulatory (Treg)-like cells. The authors used CRISPR/Cas9 gene editing to insert the long terminal repeat (LTR) and the major splice donor site (MSD) of HIV into primary human CD4+ T cells. T cells with HIV LTR-MSD integrated within BACH2 (BACH2-edited cells) showed enhanced proliferation compared with those with integration into STAT5B (STAT5B-edited cells). Analysis of the BACH2-edited cells revealed decreased IL7R and increased CD25 expression along with increased IL10 production, indicative of a Treg phenotype. BACH2-edited cells had enhanced expression of FOXP3, HELIOS, and CTLA-4 compared with STAT5B-edited cells. The BACH2-edited population showed an increased proportion of CD25high/CD127low cells, confirming that BACH2 editing induces a Treg-like phenotype in human T cells. The enhanced proliferative capability of BACH2-edited cells correlated with increased cell activation. Together, these data provide a mechanism by which a specific HIV integration event may lead to expansion and persistence of a clonally derived Treg-like cell population within infected individuals.

Steroid-insensitive severe asthma is characterized by eosinophil and neutrophil infiltration. In this Top Read, Lewis et al. (p. 1525) showed that arginine methyltransferase 5 (PRMT5) in CD4+ T cells is required for severe eosinophilic/neutrophilic lung inflammation. The authors showed that PRMT5 and its activity is upregulated in the lungs during severe lung inflammation. Mice with CD4+ T cell–deletion of PRMT5 had reduced IL-17A, leading to decreased eosinophilic and neutrophilic lung infiltration. PRMT5 promoted high pulmonary sterol metabolic activity, RORγt, and Th17 responses. Altogether, the data suggest that PRMT5 is an important mediator in severe allergic lung inflammation and could be a potential therapeutic target for severe asthma and other Th17-mediated diseases.

In this Top Read, Rocca et al. (p. 1802) investigated whether the combinatorial diversity of NK cell receptors influences their antitumor responses. They examined responses in 444 murine NK cell subsets, as defined by combinations of 12 receptors, to various genetically diverse tissues. They found that NK cell receptor repertoires do not dictate tumor specificity, but rather influence NK intrinsic reactivity. NK cells specializing in cytotoxicity preferentially expressed CD27, NKG2A, and DNAM-1. In contrast, specialized IFN-γ–producing NK cells expressed CD11b and KLRG1. Expression of educating receptors Ly49C, Ly49I, and NKG2A also correlated with IFN-γ production. However, IFN-γ production was suppressed when Ly49A, Ly49F, and Ly49G2 were not engaged. Finally, the authors showed that IL-15 stimulation broadly boosted NK cell reactivity against tumors, especially for the NK subsets that were largely unreactive in the absence of the cytokine. This study has further uncovered receptor-based mechanisms that govern NK cell reactivity, which could lead to novel NK cell–based therapeutics.

Human fetal liver–derived CD34+ cells are often used in the creation of mice with humanized immune systems (Hu/Hu). However, the use of adult bone marrow (aBM) as the donor population has the advantage of creating personalized immune (PI) mice, which can be used to study immune system function and pathogenesis. In this Top Read, Nauman et al. (p. 1652) devised a strategy to optimize immune reconstitution of aBM in PI mice. Although aBM had fewer hematopoietic stem cells than the human fetal liver–derived CD34+ cells, aBM did expand upon transfer into PI mice. However, early posttransplant PI mice showed a deficiency in APCs, such as monocyte and B cell populations, compared with Hu/Hu mice. After providing coinjection of additional mesenchymal stromal cells, along with IL-3, GM-CSF, and SCF, the APC reconstitution of PI mice was similar to the unsupported Hu/Hu mice transplanted with fetal liver–derived CD34+ cells. These data provide a better understanding of the requirements for human stem cell engraftment, as well as a potential method for creating humanized mouse models to study both normal and pathogenic human immunology.

In this Top Read, Vardam-Kaur et al. (p. 1686) showed that the extracellular ATP receptor P2RX7 drives CD8+ central memory (Tcm) and resident memory CD8+ T (Trm) cell formation. In early effector CD8+ T cells, P2RX7hi memory precursors preferentially differentiated to Tcm and Trm cells to a lesser extent compared with P2RX7lo memory precursors. Effector T cells expressing the highest levels of P2RX7 are confined to the peak effector phase. These CD62L+ memory precursors preferentially form Tcm cells. In P2rx7−/− T cells, Tcm and Trm differentiation was defective. However, upon Zeb2 knockdown, the defective Tcm and Trm formation in P2rx7−/− T cells was reversed, indicating that P2RX7 negatively regulates Zeb2 expression. Finally, the authors showed that P2RX7 partially negatively regulates Zeb2 via TGF-β signaling in early effector CD8+ T cells. Together, the authors’ data showed that P2rx7 expression levels may differentially promote CD8+ Tcm and Trm memory cell formation.

In this Top Read, Xie et al. (p. 1790) performed mass cytometry by time of flight (CyTOF) analysis of blood, gut, and genital T cells from HIV+ antiretroviral therapy–treated women. Flow Self-Organizing Maps (FlowSOM) clustering analysis revealed distinct clusters for blood T cells, distinguishing them from those residing in tissues. Gut samples contained more CD4+ and CD8+ T resident memory cells (Trm) than the female reproductive tract (FRT), although in both tissues the Trm mainly consisted of T effector memory cells expressing CD69. Because Trm from the FRT did not highly express CD103, the authors hypothesized that CD69+CD103+ Trm cells are elevated in tissues with high microbiome load. Conversely, the FRT Trm preferentially expressed PD1 compared with gut Trm, suggesting that the FRT may be more tolerogenic than the gut. Together, the findings demonstrate that resident T cells in different mucosal sites adopt distinct states, including their levels of tolerization.

In this Top Read by Borden et al. (p. 1813), the authors developed a new mathematical model that better predicts patient responsiveness to immunotherapy based on neoantigen immunogenicity. The authors mined multiple cancer patient datasets that contained numerous experimentally determined neoantigen characteristics. A regularized regression analysis was applied to the collection of characteristics and it demonstrated that three factors best correlated with immunogenicity: neoantigen:MHC class I binding affinity, binding stability, and tumor neoantigen expression level. Input of these parameters into the model returned a NeoScore for each neoantigen. Using previous datasets of patient responses to checkpoint inhibition immunotherapy, a calculated NeoScore, rather than mutational burden, best predicted patient response to therapy. These results provide a foundation for better identifying neoantigens with the greatest potential for effective antitumor immunotherapy.