The NR4A family of orphan nuclear receptors (Nr4a1-3) plays redundant roles to establish and maintain Treg identity; deletion of multiple family members in the thymus results in Treg deficiency and a severe inflammatory disease. Consequently, it has been challenging to unmask redundant functions of the NR4A family in other immune cells. Here we use a competitive bone marrow chimera strategy, coupled with conditional genetic tools, to rescue Treg homeostasis and unmask such functions. Unexpectedly, chimeras harboring Nr4a1–/– Nr4a3–/– (DKO) bone marrow develop autoantibodies and a systemic inflammatory disease despite a replete Treg compartment of largely wild-type origin. This disease differs qualitatively from that seen with Treg-deficiency and is B cell-extrinsic. Negative selection of DKO thymocytes is profoundly impaired in a cell-intrinsic manner. Consistent with escape of self-reactive T cells into the periphery, DKO T cells with functional, phenotypic, and transcriptional features of anergy accumulate in chimeric mice. Nevertheless, we observe upregulation of genes encoding inflammatory mediators in anergic DKO T cells, and DKO T cells exhibit enhanced capacity for IL-2 production. These studies reveal cell-intrinsic roles for the NR4A family in both central and peripheral T cell tolerance, and demonstrate that each is essential to preserve immune homeostasis.
Ryosuke Hiwa, Hailyn V. Nielsen, James L. Mueller, Ravi Mandla, Julie Zikherman
Innate immunity and chronic inflammation are involved in atherosclerosis and atherothrombosis leading to target organ damage in essential hypertension (EH). However, the role of neutrophils in EH is still elusive. We investigated the association between angiotensin II (Ang II) and neutrophil extracellular traps (NETs) in pathogenesis of EH. Plasma samples, kidney biopsies and surgical specimens of abdominal aortic aneurysms (AAA) from EH patients were used. Cell-based assays, NETs/human aortic endothelial cells co-cultures and in situ studies were performed. Increased plasma levels of NETs and tissue factor (TF) activity were detected in untreated, newly-diagnosed, EH patients. Stimulation of control neutrophils with plasma from untreated EH patients generated TF-enriched NETs promoting endothelial collagen production. Ang II induced NETosis in vitro via a reactive oxygen species (ROS)/peptidylarginine deiminase type 4 and autophagy-dependent pathway. Circulating NETs and thrombin generation levels were reduced significantly in EH patients starting treatment with Ang II receptor blockers, whereas their plasma was unable to trigger procoagulant NETs. Moreover, TF-bearing NETotic neutrophils/remnants were accumulated in sites of interstitial renal fibrosis and in the subendothelial layer of AAA. These data reveal the important pathogenic role of Ang II/ROS/NETs/TF axis in EH, linking thromboinflammation with endothelial dysfunction and fibrosis.
Akrivi Chrysanthopoulou, Eugenia Gkaliagkousi, Antonios Lazaridis, Stella Arelaki, Panagiotis Pateinakis, Maria Ntinopoulou, Alexandros Mitsios, Christina Antoniadou, Christos Argyriou, George S. Georgiadis, Vasileios Papadopoulos, Alexandra Giatromanolaki, Konstantinos Ritis, Panagiotis Skendros
Immunotherapies are needed in the clinic that effectively suppress beta cell autoimmunity and reestablish long-term self-tolerance in type 1 diabetes. We previously demonstrated that nondepleting αCD4 and αCD8α antibodies establish rapid and indefinite remission in recent-onset diabetic NOD mice. Diabetes reversal by coreceptor therapy (CoRT) is induced by suppression of pathogenic effector T cells (Teff) and the selective egress of T cells from the pancreatic lymph nodes and islets that remain free of infiltration long-term. Here, we defined CoRT-induced events regulating early Teff function and pancreatic residency, and long-term tolerance. TCR-driven gene expression controlling autoreactive Teff expansion and proinflammatory activity was suppressed by CoRT, and islet T cell egress was sphingosine-1 phosphate-dependent. In both murine and human T cells, CoRT upregulated the Foxo1 transcriptional axis, which in turn was required for suppression and efficient pancreatic egress of Teff. Interestingly, long-term tolerance induced in late-preclinical NOD mice was marked by reseeding of the pancreas by a reduced CD8+ Teff pool exhibiting an exhausted phenotype. Notably, PD-1 blockade, which rescues exhausted Teff, resulted in diabetes onset in protected animals. These findings demonstrate that CoRT has distinct intrinsic effects on Teff that impact events early in induction and later in maintenance of self-tolerance.
Matthew Clark, Charles J. Kroger, Qi Ke, Rui Zhang, Karen Statum, J. Justin Milner, Aaron J. Martin, Bo Wang, Roland Tisch
Rationale. The importance of the adaptative T cell response in the control and resolution of viral infection has been well-established. However, the nature of T cell-mediated viral control mechanisms in life-threatening stages of COVID-19 has yet to be determined. Objective. The aim of the present study was to determine the function and phenotype of T cell populations associated with survival or death of COVID-19 patients under intensive care as a result of phenotypic and functional profiling by mass cytometry. Findings. Increased frequencies of circulating, polyfunctional, CD4+CXCR5+HLA-DR+ stem cell memory T cells (TSCM) and decreased proportions of Granzyme-B and Perforin-expressing effector memory T cells (TEM) were detected in recovered and deceased patients, respectively. The higher abundance of polyfunctional CD8+PD-L1+CXCR3+ T effector cells, CXCR5+HLA-DR+ TSCM, as well as anti-nucleocapsid (NC) cytokine-producing T cells permitted to differentiate between recovered and deceased patients. The results from a principal component analysis showed an imbalance in the T cell compartment allowed for the separation of recovered and deceased patients. The paucity of circulating CD8+PD-L1+CXCR3+ Teff-cells and NC-specific CD8+ T-cells accurately forecasts fatal disease outcome. Conclusion. This study provides insight into the nature of the T cell populations involved in the control of COVID-19 and therefor might impact T cell-based vaccine designs for this infectious disease.
Lucille Adam, Pierre Rosenbaum, Paul Quentric, Christophe Parizot, Olivia Bonduelle, Noëlline Guillou, Aurelien Corneau, Karim Dorgham, Makoto Miyara, Charles-Edouard Luyt, Amélie Guihot, Guy Gorochov, Christophe Combadière, Behazine Combadière
Type-2 dendritic cells (DC2s) comprise the majority of conventional DCs within most tumors; however, little is known about their ability to initiate and sustain anti-tumor immunity as most studies have focused on antigen cross-presenting Type-1 DCs (DC1s). Here we report that DC2 infiltration identified by analysis of multiple human cancer data sets showed a significant correlation with survival across multiple human cancers, with the benefit being seen in tumors resistant to cytotoxic T cell control. Characterization of DC subtype infiltration into an immunotherapy-resistant model of breast cancer revealed that impairment of DC1s through two unique models resulted in enhanced DC2 functionality and improved tumor control. Batf3-deficiency depleted intratumoral DC1s led to increased DC2 lymph node migration and CD4+ T cell activation. Enhancing DC2 stimulatory potential by genetic deletion of Hsp90b1 (encoding molecular chaperon GP96) led to a similar enhancement of T cell immunity and improved survival in a spontaneous breast cancer model. This data highlights the therapeutic and prognostic potential of DC2s within checkpoint blockade-resistant tumors.
Stephen Iwanowycz, Soo Ngoi, Yingqi Li, Megan Hill, Christopher Koivisto, Melodie Parrish, Beichu Guo, Zihai Li, Bei Liu
A major γδ T cell population in human adult blood are the Vγ9Vδ2 T cells that are activated and expanded in a T cell receptor (TCR)-dependent manner by microbe- and endogenous-derived phosphorylated prenyl metabolites (phosphoantigens). Vγ9Vδ2 T cells are also abundant in human fetal peripheral blood, but compared to their adult counterparts they have a distinct developmental origin, are hyporesponsive towards in vitro phosphoantigen exposure and they do not possess a cytotoxic effector phenotype. In order to obtain insight into the role of Vγ9Vδ2 T cells in the human fetus, we investigated their response to in utero infection with the phosphoantigen-producing parasite Toxoplasma gondii (T. gondii). Vγ9Vδ2 T cells expanded strongly in face with congenital T. gondii infection which was associated with differentiation towards potent cytotoxic effector cells. The Vγ9Vδ2 T cell expansion in utero resulted in a fetal footprint with public germline-encoded clonotypes in the Vγ9Vδ2 TCR repertoire 2 months after birth. Overall, our data indicate that the human fetus, from early gestation onwards, possesses public Vγ9Vδ2 T cells that acquire effector functions following parasite infections.
Ling Ma, Maria Papadopoulou, Martin Taton, Francesca Genco, Arnaud Marchant, Valeria Meroni, David Vermijlen
Neutrophils are produced in the bone marrow (BM) in a process called granulopoiesis, in which progenitor cells sequentially develop into mature neutrophils. During the developmental process, which is finely regulated by distinct transcription factors, neutrophils acquire the ability to exit the BM, properly distribute throughout the body, and migrate to infection sites. Previous studies have demonstrated that CD40 ligand (CD40L) influences hematopoiesis and granulopoiesis. Here, we investigate the effect of CD40L on neutrophil development and trafficking by performing functional and transcriptome analyses. We found that CD40L signaling plays an essential role in the early stages of neutrophil generation and development in the BM. Moreover, CD40L modulates transcriptional signatures, indicating that this molecule enables neutrophils to traffic throughout the body and to migrate in response to inflammatory signals. Thus, our study provides new insights into the complex relationships between CD40L signaling and granulopoiesis and suggests a novel and non-redundant role of CD40L signaling in neutrophil development and function.
Tábata T. França, Ashraf Al-Sbiei, Ghada Bashir, Yassir A. Mohamed, Ranieri C. Salgado, Lucila A. Barreiros, Sarah M. da Silva Napoleão, Cristina W. Weber, Janáira F.S. Ferreira, Carolina S. Aranda, Carolina Prando, Mayra B. de Barros Dorna, Igor Jurisica, Maria J. Fernandez-Cabezudo, Hans D. Ochs, Antonio Condino-Neto, Basel K. Al-Ramadi, Otavio Cabral-Marques
Diagnosis of organ transplant rejection relies upon biopsy approaches to confirm alloreactive T cell infiltration in the graft. Immune molecular monitoring is under investigation to screen for rejection, though these techniques have suffered from low specificity and lack of spatial information. ImmunoPET utilizing antibodies conjugated to radioisotopes has the potential to improve early and accurate detection of graft rejection. ImmunoPET is capable of noninvasively visualizing the dynamic distribution of cells expressing specific immune markers in the entire body over time. In this work, we identify and characterize OX40 as a surrogate biomarker for alloreactive T cells in organ transplant rejection and monitor its expression by utilizing immunoPET. In a dual murine heart transplant model that has both syngeneic and allogeneic hearts engrafted in bilateral ear pinna on the recipients, OX40 immunoPET clearly depicted alloreactive T cells in the allograft and draining lymph node that were not observed in their respective isograft counterparts. OX40 immunoPET signals also reflected the subject’s immunosuppression level with tacrolimus in this study. OX40 immunoPET is a promising approach that may bridge molecular monitoring and morphological assessment for improved transplant rejection diagnosis.
Toshihito Hirai, Aaron T. Mayer, Tomomi W. Nobashi, Po-Yu Lin, Zunyu Xiao, Tomokatsu Udagawa, Kinya Seo, Federico Simonetta, Jeanette Baker, Alan G. Cheng, Robert S. Negrin, Sanjiv S. Gambhir
Heart transplantation is the optimal therapy for patients with end-stage heart disease, but its long-term outcome remains inadequate. Recent studies have highlighted the importance of the melanocortin receptors (MCRs) in inflammation, but how MCRs regulate the balance between alloreactive T cells and Tregs, and whether they impact chronic heart transplant rejection, is unknown. Here, we found that Tregs express MC2R, and MC2R expression was highest among all MCRs by Tregs. Our data indicate that adrenocorticotropic hormone (ACTH), the sole ligand for MC2R, promoted the formation of Tregs by increasing the expression of IL-2Rα (CD25) in CD4+ T cells and activation of STAT5 in CD4+CD25+ T cells. ACTH treatment also improved the survival of heart allografts and increased the formation of Tregs in CD28KO mice. ACTH treatment synergized with the tolerogenic effect of CTLA-4–Ig, resulting in long-term survival of heart allografts and an increase in intragraft Tregs. ACTH administration also demonstrated higher prolongation of heart allograft survival in transgenic mouse recipients with both complete KO and conditional KO of PI3Kγ in T cells. Finally, ACTH treatment reduced chronic rejection markedly. These data demonstrate that ACTH treatment improved heart transplant outcomes, and this effect correlated with an increase in Tregs.
Jing Zhao, Liwei Jiang, Mayuko Uehara, Naima Banouni, Basmah S. Al Dulaijan, Jamil Azzi, Takaharu Ichimura, Xiaofei Li, Petr Jarolim, Paolo Fiorina, Stefan G. Tullius, Joren C. Madsen, Vivek Kasinath, Reza Abdi
Background Immunomodulatory therapy may help prevent heart failure (HF). Data on immune cells and myocardial remodeling in older adults with cardiovascular risk factors are limited.Methods In the Multi-Ethnic Study of Atherosclerosis cohort, 869 adults had 19 peripheral immune cell subsets measured and underwent cardiac MRI during the baseline exam, of which 321 had assessment of left ventricular global circumferential strain (LV-GCS). We used linear regression with adjustment for demographics, cardiovascular risk factors, and cytomegalovirus serostatus to evaluate the cross-sectional association of immune cell subsets with left ventricular mass index (LVMI) and LV-GCS.Results The average age of the cohort was 61.6 ± 10.0 years and 53% were women. Higher proportions of γ/δ T cells were associated with lower absolute (worse) LV-GCS (–0.105% [95% CI –0.164%, –0.046%] per 1 SD higher proportion of γ/δ T cells, P = 0.0006). This association remained significant after Bonferroni’s correction. Higher proportions of classical monocytes were associated with worse absolute LV-GCS (–0.04% [95% CI –0.07%, 0.00%] per 1 SD higher proportion of classical monocytes, P = 0.04). This did not meet significance after Bonferroni’s correction. There were no other significant associations with LV-GCS or LVMI.Conclusion Pathways associated with γ/δ T cells may be potential targets for immunomodulatory therapy targeted at HF prevention in populations at risk.Funding Contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 and grant R01 HL98077 from the National Heart, Lung, and Blood Institute/NIH and grants KL2TR001424, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences/NIH.
Arjun Sinha, Adovich S. Rivera, Margaret F. Doyle, Colleen Sitlani, Alison Fohner, Sally A. Huber, Nels C. Olson, Joao A.C. Lima, Joseph A. Delaney, Matthew J. Feinstein, Sanjiv J. Shah, Russel P. Tracy, Bruce M. Psaty
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