The human adult immune system maintains normal T-cell counts and compensates for T-cell loss over lifetime mainly through peripheral homeostatic proliferation after the ability of the thymus to generate new T cells has rapidly declined at adolescence. This process is mainly driven by STAT5-activating cytokines, most importantly IL-7, and is very effective in maintaining a large naïve CD4 T cell compartment into older age. Here, we describe that naïve CD4 T cells undergo adaptations to optimize IL-7 responses by upregulating the guanine-nucleotide exchange factor PREX1 at older age. PREX1 promotes nuclear translocation of phosphorylated STAT5, thereby supporting homeostatic proliferation in response to IL-7. Through the same mechanism, increased expression of PREX1 also biases naïve cells to differentiate into effector T cells. These findings are consistent with the concept that primarily beneficial adaptations during aging, i.e., improved homeostasis, account for unfavorable functions of the aged immune system, in this case biased differentiation.
Huimin Zhang, Hirohisa Okuyama, Abhinav Jain, Rohit R. Jadhav, Bowen Wu, Ines Sturmlechner, Jose Morales, Shozo Ohtsuki, Cornelia M. Weyand, Jörg J. Goronzy
Inappropriate immune activity is key in the pathogenesis of multiple diseases and is typically driven by excess inflammation and/or autoimmunity. IL-1 is often the effector due to its powerful role in both innate and adaptive immunity, and thus is tightly controlled at multiple levels. IL-1R2 antagonises IL-1, but effects of losing this regulation is unknown. We find IL-1R2 resolves inflammation by rapidly scavenging free IL-1. Specific IL-1R2 loss in germinal centre (GC) T follicular regulatory (Tfr) cells increases the GC response after a first, but not booster, immunisation, with more T follicular helper (Tfh) cells, GC B cells and antigen-specific antibodies, which is reversed upon IL-1 blockade. However, IL-1 signalling is not obligate for GC reactions, as wildtype and Il1r1–/– mice show equivalent phenotypes, suggesting GC IL-1 is normally restrained by IL-1R2. Fascinatingly, germline Il1r2–/– mice do not show this phenotype, but conditional Il1r2 deletion in adulthood recapitulates it, implying compensation during development counteracts IL-1R2 loss. Finally, patients with ulcerative colitis or Crohn’s disease have lower serum IL-1R2. Together, we show that IL-1R2 controls important aspects of innate and adaptive immunity, and that IL-1R2 level may contribute to human disease propensity and/or progression.
Katerina Pyrillou, Melanie Humphry, Lauren A. Kitt, Amanda Rodgers, Meritxell Nus, Martin R. Bennett, Kenneth G.C. Smith, Paul A. Lyons, Ziad Mallat, Murray C.H. Clarke
Atopic dermatitis (AD) is a persistent skin disease typified by symptoms of dry skin and recurrent eczema. AD patients are at heightened risk for Staphylococcus aureus (S. aureus) infection. Group 2 innate lymphoid cells (ILC2s) are mainly activated by epithelial cell-derived cytokines IL-33 and involved in the pathogenesis of AD. However, little is known about the effect of skin delipidization on the epithelial cell-derived cytokines and dermal ILC2s in AD. In our study, we investigated the mechanism by which S. aureus infection modulates and exacerbates the pathogenesis of dry skin, leading to type 2 inflammation in the context of innate immunity. In vivo, we found that S. aureus infection aggravated delipidization-induced dermal IL-33 release and dermal ILC2 accumulation, which exacerbated skin inflammation. We also noticed that Il33f/fK14cre mice and Tlr2–/– mice exhibited attenuated skin inflammation. In vitro, treatment with necroptosis inhibitors reduced IL-33 release from S. aureus-infected keratinocytes. Mechanistically, we observed an increase in the necroptosis-associated kinases, MLKL and RIPK3, in S. aureus-infected mice, indicating that IL-33 release was associated with necroptotic cell death responses. Our results reveal that S. aureus infection-elicited keratinocyte necroptosis contributes to IL-33-mediated type 2 inflammation, which exacerbates the pathogenesis of dry skin.
Chia-Hui Luo, Alan Chuan-Ying Lai, Chun-Chou Tsai, Wei-Yu Chen, Yu-Shan Chang, Ethan Ja-Chen Chung, Ya-Jen Chang
Pattern-Recognition Receptor responses are profoundly attenuated before the third trimester of gestation, in the relatively low oxygen human fetal environment. However, the mechanisms regulating these responses are uncharacterized. Herein, genome-wide transcription and functional metabolic experiments in primary neonatal monocytes linked the negative mTOR regulator DDIT4L to metabolic stress, cellular bioenergetics and innate immune activity. Using genetically engineered monocytic U937 cells, we confirmed that DDIT4L overexpression altered mitochondrial dynamics, suppressing their activity, and blunted LPS-induced cytokine responses. We also showed that monocyte mitochondrial function is more restrictive in earlier gestation, resembling the phenotype of DDIT4L-overexpressing U937 cells. Gene expression analyses in neonatal granulocytes, and lung macrophages in preterm infants confirmed upregulation of the DDIT4L gene in the early postnatal period, and also suggested a potential protective role against inflammation-associated chronic neonatal lung disease. Together, these data show that DDIT4L regulates mitochondrial activity and provide the first direct evidence for its potential role regulating innate immune activity in myeloid cells during development.
Christina Michalski, Claire Cheung, Ju Hee Oh, Emma Ackermann, Constantin R. Popescu, Anne-Sophie Archambault, Martin A. Prusinkiewicz, Rachel Da Silva, Abdelilah Majdoubi, Marina Viñeta Paramo, Rui Yang Xu, Frederic Reicherz, Annette E. Patterson, Liam Golding, Ashish A. Sharma, Chinten J. Lim, Paul C. Orban, Ramon I. Klein Geltink, Pascal M. Lavoie
Acute bacterial orchitis (AO) is a prevalent cause of intra-scrotal inflammation, often resulting in sub- or infertility. A frequent cause eliciting AO is uropathogenic Escherichia coli (UPEC), a gram negative pathovar, characterized by the expression of various iron acquisition systems to survive in a low-iron environment. On the host side, iron is tightly regulated by iron regulatory proteins (IRP) 1 and 2 and these factors are reported to play a role in testicular and immune cell function, however, their precise role remains unclear. Here, we showed in a mouse model of UPEC-induced orchitis that the absence of IRP1 results in reduced immune response and testicular damage. Compared to infected wild-type (WT)-mice, testis of UPEC-infected Irp1–/– mice showed impaired ERK signaling. Conversely, IRP2 deletion led to a stronger inflammatory response. Notably, differences in immune cell infiltrations were observed among the different genotypes. In contrast to WT and Irp2–/– mice, no increase in monocytes and neutrophils was detected in testis of Irp1–/– mice upon UPEC-infection. Interestingly, in Irp1–/– UPEC-infected testis, we observed an increase in a subpopulation of macrophages (F4/80+ CD206+) associated with anti-inflammatory and wound-healing activities compared to WT. These findings suggest that IRP1 deletion may protect against UPEC-induced inflammation by modulating ERK signaling and dampening the immune response.
Niraj Ghatpande, Aileen Harrer, Bar Azoulay-Botzer, Noga Guttmann-Raviv, Sudhanshu Bhushan, Andreas Meinhardt, Esther G. Meyron-Holtz
Adoptive transfer of immune regulatory cells can prevent or ameliorate graft-versus-host disease (GVHD), which remains the main cause of non-relapse mortality after allogeneic hematopoietic stem-cell transplantation. Mucosal-associated invariant T cells (MAITs) were recently associated with tissue repair capacities and with lower rates of GVHD in humans. Here, we analyzed the immunosuppressive effect of MAITs in an in vitro model of alloreactivity and explored their adoptive transfer in a preclinical xenogeneic-GVHD model. We found that MAIT cells, whether freshly purified or shortly expanded, dose-dependently inhibited proliferation and activation of alloreactive T cells. In immunodeficient mice injected with human PBMCs, MAITs strongly delayed GVHD onset and severity when transferred early after PBMC injection, but could also control ongoing GVHD when transferred at delayed time points. This effect was associated with decreased proliferation and effector function of human T cells infiltrating tissues of diseased mice and was correlated with lower circulating IFN-γ and TNF-α levels, and increased IL-10 levels. MAITs acted partly in a contact-dependent manner, which likely required direct interaction of their TCR with MR1 induced on host-reactive T cells. These results support the setup of clinical trials using MAITs as universal therapeutic tools to control severe GVHD or mucosal inflammatory disorders.
Nana Talvard-Balland, Marion Lambert, Mathieu F. Chevalier, Norbert Minet, Marion Salou, Marie Tourret, Armelle Bohineust, Idan Milo, Véronique Parietti, Thomas Yvorra, Gérard Socié, Olivier Lantz, Sophie Caillat-Zucman
A robust sterile inflammation underlies myocardial ischemia and reperfusion injury (MIRI). Several subsets of B-cells possess the immune-regulatory capacity that limits tissue damage, yet the role of B-cells in MIRI remains elusive. Here, we sought to elucidate the contribution of B-cells to the MIRI by transient ligation of the left anterior descending in the B-cell depleted or deficient mice. Following ischemia and reperfusion (I/R), regulatory B-cells are rapidly recruited to the heart. B-cell-depleted or deficient mice exhibited exacerbated tissue damage, adverse cardiac remodeling, and an augmented inflammatory response after I/R. Rescue and chimeric experiments indicated that the cardioprotective effect of B-cells was not solely dependent on IL10. Coculture experiments demonstrated that B-cells induced neutrophil apoptosis through contact-dependent interaction, subsequently promoting reparative macrophage polarization by facilitating the phagocytosis of neutrophils by macrophages. The in-vivo cardioprotective effect of B-cells was absent in absence of neutrophils after I/R. Mechanistically, ligand-receptor imputation identified FCER2A as a potential mediator of interactions between B-cells and neutrophils. Blocking FCER2A on B-cells resulted in a reduction in the percentage of apoptotic neutrophils, contributing to the deterioration of cardiac remodeling. Our findings unveil a potential cardioprotective role of B-cells in myocardial I/R through mechanisms involving FCER2A, neutrophil, and macrophage.
Fangyang Huang, Jialiang Zhang, Hao Zhou, Tianyi Qu, Yan Wang, Kexin Jiang, Yutong Liu, Yuan Ning Xu, Mao Chen, Li Chen
Regulatory T (Treg) cells can facilitate transplant tolerance and attenuate autoimmune- and inflammatory diseases. Therefore, it is clinically relevant to stimulate Treg cell expansion and function in vivo and to create therapeutic Treg cell products in vitro. We report that TNF receptor 2 (TNFR2) is a unique costimulus for naïve, thymus-derived (t)Treg cells from human blood that promotes their differentiation into non-lymphoid tissue (NLT)-resident effector Treg cells, without Th-like polarization. In contrast, CD28 costimulation maintains a lymphoid tissue (LT)-resident Treg cell phenotype. We base this conclusion on transcriptome and proteome analysis of TNFR2- and CD28-costimulated CD4+ tTreg cells and conventional T (Tconv) cells, followed by bioinformatic comparison with published transcriptomic Treg cell signatures from NLT and LT in health and disease, including autoimmunity and cancer. These analyses illuminated that TNFR2 costimulation promotes tTreg cell capacity for survival, migration, immunosuppression and tissue regeneration. Functional studies confirmed improved migratory ability of TNFR2-costimulated tTreg cells. Flow cytometry validated the presence of the TNFR2-driven tTreg cell signature in effector/memory Treg cells from the human placenta as opposed to blood. Thus, TNFR2 can be exploited as driver of NLT-resident tTreg cell differentiation for adoptive cell therapy or antibody-based immunomodulation in human disease.
Mark Mensink, Lotte J. Verleng, Ellen Schrama, George M.C. Janssen, Rayman T.N. Tjokrodirijo, Peter A. van Veelen, Qinyue Jiang, M. Fernanda Pascutti, Marie-Louise van der Hoorn, Michael Eikmans, Sander de Kivit, Jannie Borst
Innate immune cells are important in the initiation and potentiation of alloimmunity in transplantation. Immediately upon organ anastomosis and reperfusion, recipient monocytes enter the graft from circulation and differentiate to inflammatory macrophages to promote allograft inflammation. However, factors that drive their differentiation to inflammatory macrophages are not understood. Here, we showed that the receptor tyrosine kinase AXL was a key driver of early intragraft differentiation of recipient infiltrating monocytes to inflammatory macrophages in the presence of allogeneic stimulation and cell-cell contact. In this context, the differentiated inflammatory macrophages were capable of efficient alloantigen presentation and allo-stimulation of T cells of the indirect pathway. Consequently, early and transient AXL inhibition with the pharmacological inhibitor bemcentinib resulted in a profound reduction of initial allograft inflammation and a significant prolongation of allograft survival in a murine heart transplant model. Our results support further investigation of AXL inhibition as part of an induction regimen for transplantation.
Collin Z. Jordan, Matthew Tunbridge, Irma Husain, Hiroki Kitai, Miriam E. Dilts, Olivia K. Fay, Koki Abe, Catherine Xiang, Jean Kwun, Tomokazu Souma, Edward B. Thorp, Xunrong Luo
BACKGROUND. T cell responses are impaired in Staphylococcus aureus-infected children, highlighting a potential mechanism of immune evasion. This study tested the hypotheses that toxin-specific antibodies protect immune cells from bacterial killing and are associated with improved T cell function following infection. METHODS.S. aureus-infected and healthy children (n = 33 each) were prospectively enrolled. During acute infection and convalescence, we quantified toxin-specific IgG levels by ELISA, antibody function using a cell-killing assay, and functional T cell responses by ELISpot. RESULTS. There were no differences in toxin-specific IgG levels or ability to neutralize toxin-mediated immune cell killing between healthy and acutely-infected children, but antibody levels and function increased following infection. Similarly, T cell function, which was impaired during acute infection, improved following infection. However, the response to infection was highly variable; up to half of children did not have improved antibody or T cell function. Serum from children with higher ɑ-hemolysin (Hla)-specific IgG levels more strongly protected immune cells against toxin-mediated killing. Importantly, children whose serum more strongly protected against toxin-mediated killing also had stronger immune responses to infection, characterized by more elicited antibody and greater improvement in T cell function following infection. CONCLUSIONS. This study demonstrates that, despite T cell impairment during acute infection, S. aureus elicits toxin-neutralizing antibodies. Individual antibody responses and T cell recovery are variable. These findings also suggest that toxin-neutralizing antibodies protect antigen-presenting cells and T cells, thereby promoting immune recovery. Finally, failure to elicit toxin-neutralizing antibodies may identify children at risk for prolonged T cell suppression. FUNDING. NIAID R01AI125489 and Nationwide Children’s Hospital.
Maureen Kleinhenz, Zhaotao Li, Usha V. Chidella, Walissa Picard, Amber Wolfe, Jill Popelka, Robin Alexander, Christopher P. Montgomery
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