The Journal of Experimental Medicine

Kim, Dongeon;Kim, Mingyo;Kim, Tae Woo;Choe, Yong-ho;Noh, Hae Sook;Jeon, Hyun Min;Kim, HyunSeok;Lee, Youngeun;Hur, Gayeong;Lee, Kyung-Mi;Shin, Kihyuk;Lee, Sang-il;Lee, Seung-Hyo

doi: 10.1084/jem.20200795pmid: 35315876

Lymph node fibroblastic reticular cells (LN-FRCs) provide functional structure to LNs and play important roles in interactions between T cells and antigen-presenting cells. However, the direct impact of LN-FRCs on naive CD4+ T cell differentiation has not been explored. Here, we show that T cell zone FRCs of LNs (LN-TRCs) express CD25, the α chain of the IL-2 receptor heterotrimer. Moreover, LN-TRCs trans-present IL-2 to naive CD4+ T cells through CD25, thereby facilitating early IL-2–mediated signaling. CD25-deficient LN-TRCs exhibit attenuated STAT5 phosphorylation in naive CD4+ T cells during T cell differentiation, promoting T helper 17 (Th17) cell differentiation and Th17 response-related gene expression. In experimental autoimmune disease models, disease severity was elevated in mice lacking CD25 in LN-TRCs. Therefore, our results suggest that CD25 expression on LN-TRCs regulates CD4+ T cell differentiation by modulating early IL-2 signaling of neighboring, naive CD4+ T cells, influencing the overall properties of immune responses.

Quattrocelli, Mattia;Wintzinger, Michelle;Miz, Karen;Panta, Manoj;Prabakaran, Ashok D.;Barish, Grant D.;Chandel, Navdeep S.;McNally, Elizabeth M.

doi: 10.1084/jem.20211906pmid: 35363257

The fat–muscle communication regulates metabolism and involves circulating signals like adiponectin. Modulation of this cross-talk could benefit muscle bioenergetics and exercise tolerance in conditions like obesity. Chronic daily intake of exogenous glucocorticoids produces or exacerbates metabolic stress, often leading to obesity. In stark contrast to the daily intake, we discovered that intermittent pulses of glucocorticoids improve dystrophic muscle metabolism. However, the underlying mechanisms, particularly in the context of obesity, are still largely unknown. Here we report that in mice with diet-induced obesity, intermittent once-weekly prednisone increased total and high-molecular weight adiponectin levels and improved exercise tolerance and energy expenditure. These effects were dependent upon adiponectin, as shown by genetic ablation of the adipokine. Upregulation of Adipoq occurred through the glucocorticoid receptor (GR), as this effect was blocked by inducible GR ablation in adipocytes. The treatment increased the muscle metabolic response of adiponectin through the CAMKK2–AMPK cascade. Our study demonstrates that intermittent glucocorticoids produce healthful metabolic remodeling in diet-induced obesity.

Churchill, Madeline J.; du Bois, Haley;Heim, Taylor A.;Mudianto, Tenny;Steele, Maria M.;Nolz, Jeffrey C.;Lund, Amanda W.

doi: 10.1084/jem.20211830pmid: 35353138

Lymphatic vessels are often considered passive conduits that flush antigenic material, pathogens, and cells to draining lymph nodes. Recent evidence, however, suggests that lymphatic vessels actively regulate diverse processes from antigen transport to leukocyte trafficking and dietary lipid absorption. Here we tested the hypothesis that infection-induced changes in lymphatic transport actively contribute to innate host defense. We demonstrate that cutaneous vaccinia virus infection by scarification activates dermal lymphatic capillary junction tightening (zippering) and lymph node lymphangiogenesis, which are associated with reduced fluid transport and cutaneous viral sequestration. Lymphatic-specific deletion of VEGFR2 prevented infection-induced lymphatic capillary zippering, increased fluid flux out of tissue, and allowed lymphatic dissemination of virus. Further, a reduction in dendritic cell migration to lymph nodes in the absence of lymphatic VEGFR2 associated with reduced antiviral CD8+ T cell expansion. These data indicate that VEGFR2-driven lymphatic remodeling is a context-dependent, active mechanism of innate host defense that limits viral dissemination and facilitates protective, antiviral CD8+ T cell responses.

Zhang, Huihui;Wei, Ran;Yang, Xinyi;Xu, Lu;Jiang, Hongchao;Li, Mengkai;Jiang, Haixia;Zhang, Haibo;Chen, Zhihong;Qian, Feng;Sun, Lei

doi: 10.1084/jem.20211828pmid: 35333296

Alveolar macrophages (AMs) are specialized tissue-resident macrophages that orchestrate the immune response in allergic inflammation and asthma. However, what signals direct AMs to cross talk with other immune cells remains unclear. Here, we report that autocrine motility factor receptor (AMFR), an endoplasmic reticulum–resident E3 ubiquitin ligase, is upregulated in AMs of asthma and is critical for this condition. AMFR deficiency significantly decreased allergy-induced T helper 2 (Th2) and eosinophilic inflammation, with less granulocyte-macrophage colony-stimulating factor (GM-CSF) production in AMs. Mechanistically, following thymic stromal lymphopoietin (TSLP) stimulation, AMFR associated directly with cytokine-inducible SH2-containing protein (CIS), induced the ubiquitination of Lys48-linked polyubiquitination of CIS, and consequently blocked the inhibitory effect of CIS on signal transducer and activator of transcription 5 (STAT5) phosphorylation and the downstream pathway activation in AMs. In conclusion, our results demonstrate that AMFR serves a crucial role in promoting inflammation in asthma through regulating AM function, and may emerge as a new potential drug target for asthma therapy.

Mann, Alexander O.;Hanna, Bola S.;Muñoz-Rojas, Andrés R.;Sandrock, Inga;Prinz, Immo;Benoist, Christophe;Mathis, Diane

doi: 10.1084/jem.20211504pmid: 35380608

Subsequent to acute injury, skeletal muscle undergoes a stereotypic regenerative process that reestablishes homeostasis. Various types of innate and adaptive immunocytes exert positive or negative influences at specific stages along the course of muscle regeneration. We describe an unanticipated role for γδT cells in promoting healthy tissue recovery after injection of cardiotoxin into murine hindlimb muscle. Within a few days of injury, IL-17A–producing γδT cells displaying primarily Vγ6+ antigen receptors accumulated at the wound site. Punctual ablation experiments showed that these cells boosted early inflammatory events, notably recruitment of neutrophils; fostered the proliferation of muscle stem and progenitor cells; and thereby promoted tissue regeneration. Supplementation of mice harboring low numbers of IL-17A+ γδT cells with recombinant IL-17A largely reversed their inflammatory and reparative defects. Unexpectedly, the accumulation and influences of γδT cells in this experimental context were microbiota dependent, unveiling an orthogonal perspective on the treatment of skeletal muscle pathologies such as catastrophic wounds, wasting, muscular dystrophies, and myositides.

Yin, Yujing;Xu, Dengqiu;Mao, Yan;Xiao, Liwei;Sun, Zongchao;Liu, Jing;Zhou, Danxia;Xu, Zhisheng;Liu, Lin;Fu, Tingting;Ding, Chenyun;Guo, Qiqi;Sun, Wanping;Zhou, Zheng;Yang, Likun;Jia, Yuhuan;Chen, Xinyi;Gan, Zhenji

doi: 10.1084/jem.20212491

Tao, Xixi;Zhang, Rui;Du, Ronglu;Yu, Tingting;Yang, Hui;Li, Jiwen;Wang, Yuhong;Liu, Qian;Zuo, Shengkai;Wang, Xi;Lazarus, Michael;Zhou, Lu;Wang, Bangmao;Yu, Ying;Shen, Yujun

doi: 10.1084/jem.20212414pmid: 35420633

Natural killer (NK) cells exhibit antifibrotic properties in liver fibrosis (LF) by suppressing activated hepatic stellate cell (HSC) populations. Prostaglandin E2 (PGE2) plays a dual role in innate and adaptive immunity. Here, we found that E-prostanoid 3 receptor (EP3) was markedly downregulated in NK cells from liver fibrosis mice and patients with liver cirrhosis. NK cell–specific deletion of EP3 aggravated hepatic fibrogenesis in mouse models of LF. Loss of EP3 selectively reduced the cytotoxicity of the CD27+CD11b+ double positive (DP) NK subset against activated HSCs. Mechanistically, deletion of EP3 impaired the adhesion and cytotoxicity of DP NK cells toward HSCs through modulation of Itga4-VCAM1 binding. EP3 upregulated Itga4 expression in NK cells through promoting Spic nuclear translocation via PKC-mediated phosphorylation of Spic at T191. Activation of EP3 by sulprostone alleviated CCL4-induced liver fibrosis in mice. Thus, EP3 is required for adhesion and cytotoxicity of NK cells toward HSCs and may serve as a therapeutic target for the management of LF.

Mysore, Vijayashree;Tahir, Suhail;Furuhashi, Kazuhiro;Arora, Jatin;Rosetti, Florencia;Cullere, Xavier;Yazbeck, Pascal;Sekulic, Miroslav;Lemieux, Madeleine E.;Raychaudhuri, Soumya;Horwitz, Bruce H.;Mayadas, Tanya N.

doi: 10.1084/jem.20210562pmid: 35404389

Monocytes undergo phenotypic and functional changes in response to inflammatory cues, but the molecular signals that drive different monocyte states remain largely undefined. We show that monocytes acquire macrophage markers upon glomerulonephritis and may be derived from CCR2+CX3CR1+ double-positive monocytes, which are preferentially recruited, dwell within glomerular capillaries, and acquire proinflammatory characteristics in the nephritic kidney. Mechanistically, the transition to immature macrophages begins within the vasculature and relies on CCR2 in circulating cells and TNFR2 in parenchymal cells, findings that are recapitulated in vitro with monocytes cocultured with TNF-TNFR2–activated endothelial cells generating CCR2 ligands. Single-cell RNA sequencing of cocultures defines a CCR2-dependent monocyte differentiation path associated with the acquisition of immune effector functions and generation of CCR2 ligands. Immature macrophages are detected in the urine of lupus nephritis patients, and their frequency correlates with clinical disease. In conclusion, CCR2-dependent functional specialization of monocytes into macrophages begins within the TNF-TNFR2–activated vasculature and may establish a CCR2-based autocrine, feed-forward loop that amplifies renal inflammation.

Chen, Yawen;Wang, Xianwei;Hao, Xiaolei;Li, Bin;Tao, Wanyin;Zhu, Shu;Qu, Kun;Wei, Haiming;Sun, Rui;Peng, Hui;Tian, Zhigang

doi: 10.1084/jem.20211805pmid: 35348580

Type 1 innate lymphoid cells (ILC1s) represent the predominant population of liver ILCs and function as important effectors and regulators of immune responses, but the cellular heterogeneity of ILC1s is not fully understood. Here, single-cell RNA sequencing and flow cytometric analysis demonstrated that liver ILC1s could be dissected into Ly49E+ and Ly49E− populations with unique transcriptional and phenotypic features. Genetic fate-mapping analysis revealed that liver Ly49E+ ILC1s with strong cytotoxicity originated from embryonic non–bone marrow hematopoietic progenitor cells (HPCs), persisted locally during postnatal life, and mediated protective immunity against cytomegalovirus infection in newborn mice. However, Ly49E− ILC1s developed from BM and extramedullary HPCs after birth, gradually replaced Ly49E+ ILC1s in the livers with age, and contained the memory subset in recall response to hapten challenge. Thus, our study shows that Ly49E dissects liver ILC1s into two unique subpopulations, with distinct origins and a bias toward neonatal innate or adult immune memory responses.

Aguilar, Oscar A.;Fong, Lam-Kiu;Ishiyama, Kenichi;DeGrado, William F.;Lanier, Lewis L.

doi: 10.1084/jem.20220022pmid: 35320345

Natural killer (NK) cells can detect antibody-coated cells through recognition by the CD16 Fc receptor. The importance of CD16 in human NK cell biology has long been appreciated, but how CD16 functions in mouse NK cells remains poorly understood. Here, we report drastic differences between human and mouse CD16 functions in NK cells. We demonstrate that one of the adaptor molecules that CD16 associates with and signals through, CD3ζ, plays a critical role in these functional differences. Using a systematic approach, we demonstrate that residues in the transmembrane domain of the mouse CD3ζ molecule prevent efficient complex formation with mouse CD16, thereby dampening receptor function. Mutating these residues in mouse CD3ζ to those encoded by human CD3ζ resulted in rescue of CD16 receptor function. We reveal that the mouse CD3ζ transmembrane domain adopts a tightly packed confirmation, preventing association with CD16, whereas human CD3ζ adopts a versatile configuration that accommodates receptor assembly.