Immunology
Abstract
African American (AA) women are disproportionally affected by obesity and hyperlipidemia, particularly in the setting of adverse social determinants of health (aSDoH) contributing to health disparities. Obesity, hyperlipidemia, and aSDoH appear to impair Natural Killer cells (NKs). As potential common underlying mechanisms are largely unknown, we sought to investigate common signaling pathways involved in NK dysfunction related to obesity and hyperlipidemia in AA women from under-resourced neighborhoods. We determined in freshly isolated NKs that obesity and measures of aSDoH are associated with a shift in NK subsets away from CD56dim/CD16+ cytotoxic NKs. Using ex vivo data, we identified LDL as a marker related to NK cell function in an AA population from under-resourced neighborhoods. Additionally, NK cells from AA women with obesity and LDL-treated NK cells displayed a loss in NK cell function. Comparative unbiased RNA sequencing analysis revealed DUSP1 as a common factor. Subsequently, chemical inhibition of DUSP1 and DUSP1 overexpression in NK cells highlighted its significance in NK cell function and lysosome biogenesis in a mTOR/TFEB-related fashion. Our data demonstrate a pathway by which obesity and hyperlipidemia in the setting of aSDoH may relate to NK dysfunction, making DUSP1 an important target for further investigation of health disparities.
Authors
Yvonne Baumer, Komudi Singh, Abhinav Saurabh, Andrew S. Baez, Cristhian A. Gutierrez-Huerta, Long Chen, Muna Igboko, Briana S. Turner, Josette A. Yeboah, Robert N. Reger, Lola R. Ortiz-Whittingham, Sahil Joshi, Marcus R. Andrews, Elizabeth M. Aquino Peterson, Christopher K.E. Bleck, Laurel G. Mendelsohn, Valerie M. Mitchell, Billy S. Collins, Neelam R. Redekar, Skyler A. Kuhn, Christian A. Combs, Mehdi Pirooznia, Pradeep K. Dagur, David S.J. Allan, Daniella Muallem-Schwartz, Richard W. Childs, Tiffany M. Powell-Wiley
Abstract
T cells are involved in protective immunity against numerous viral infections. Data regarding functional roles of human T cells in SARS-CoV-2 (SARS2) viral clearance in primary COVID-19 are limited. To address this knowledge gap, we assessed samples for associations between SARS2 upper respiratory tract viral RNA levels and early virus-specific adaptive immune responses for 95 unvaccinated clinical trial participants with acute primary COVID-19 aged 18–86 years old, approximately half of whom were considered at high risk for progression to severe COVID-19. Functionality and magnitude of acute SARS2-specific CD4+ and CD8+ T cell responses were evaluated, in addition to antibody responses. Most individuals with acute COVID-19 developed SARS2-specific T cell responses within 6 days of COVID-19 symptom onset. Early CD4+ T cell and CD8+ T cell responses were polyfunctional, and both strongly associated with reduced upper respiratory tract SARS2 viral RNA, independent of neutralizing antibody titers. Overall, these findings provide evidence for protective roles for circulating SARS2-specific CD4+ and CD8+ T cells during acute COVID-19.
Authors
Sydney I. Ramirez, Paul G. Lopez, Farhoud Faraji, Urvi M. Parikh, Amy Heaps, Justin Ritz, Carlee Moser, Joseph J. Eron, David Wohl, Judith Currier, Eric S. Daar, Alex Greninger, Paul Klekotka, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, Bjoern Peters, Michael D. Hughes, Kara W. Chew, Davey M. Smith, Shane Crotty, for the Accelerating COVID-19 Therapeutic Interventions and Vaccines-2 (ACTIV-2)/A5401 Study Team
Abstract
Specialized memory CD4 T cells that reside long-term within tissues are critical components of immunity at portals of pathogen entry. In the lung, such tissue-resident memory (TRM) cells are activated rapidly after infection and promote local inflammation to control pathogen levels before circulating T cells can respond. However, optimal clearance of Influenza A virus can require TRM and responses by other virus-specific T cells that reach the lung only several days after their activation in secondary lymphoid organs. Whether local CD4 TRM sentinel activity can impact the efficiency of T cell activation in secondary lymphoid organs is not clear. Here, we found that recognition of antigen by influenza -primed TRM in the airways promotes more rapid migration of highly activated antigen-bearing dendritic cells to the draining lymph nodes. This in turn accelerated the priming of naive T cells recognizing the same antigen, resulting in newly activated effector T cells reaching the lungs earlier than in mice not harboring TRM. Our findings thus reveal a circuit linking local and regional immunity whereby antigen recognition by TRM improves effector T cell recruitment to the site of infection though enhancing the efficiency of antigen presentation in the draining lymph node.
Authors
Caroline M. Finn, Kunal Dhume, Eugene Baffoe, Lauren A. Kimball, Tara M. Strutt, K. Kai McKinstry
Abstract
In systemic lupus erythematosus (lupus), environmental effects acting within a permissive genetic background lead to autoimmune dysregulation. Dysfunction of CD4+ T cells contributes to pathology by providing help to autoreactive B and T cells, and CD4+ T cell dysfunction coincides with altered DNA methylation and histone modifications of select gene loci. However, chromatin accessibility states of distinct T cell subsets and mechanisms driving heterogeneous chromatin states across patients remain poorly understood. We defined the transcriptome and epigenome of multiple CD4+ T cell populations from lupus patients and healthy individuals. Most lupus patients, regardless of disease activity, had enhanced chromatin accessibility bearing hallmarks of inflammatory cytokine signals. Single cell approaches revealed that chromatin changes extended to naive CD4+ T cells; uniformly affecting naive subpopulations. Transcriptional data and cellular and protein analyses suggested that the TNF family members, TNFɑ, LIGHT, and TWEAK, were linked to observed molecular changes and the altered lupus chromatin state. However, we identified a patient subgroup prescribed angiotensin receptor blockers (ARBs) which lacked TNF-linked lupus chromatin accessibility features. These data raise questions about the role of lupus-associated chromatin changes in naive CD4+ T cell activation and differentiation and implicate ARBs in the regulation of disease-driven epigenetic states.
Authors
Andrew P. Hart, Jonathan J. Kotzin, Steffan W. Schulz, Jonathan S. Dunham, Alison L. Keenan, Joshua F. Baker, Andrew D. Wells, Daniel P. Beiting, Terri M. Laufer
Abstract
Regulatory T (Treg) cells are essential for maternal immune tolerance of the fetus and placenta. In preeclampsia, aberrant Treg cell tolerance is implicated, but whether and how Treg cells affect the uterine vascular dysfunction thought to precede placental impairment and maternal vasculopathy is unclear. We utilized Foxp3DTR mice to test the hypothesis that Treg cells are essential regulators of decidual spiral artery adaptation to pregnancy. Transient Treg cell depletion during early placental morphogenesis caused impaired remodeling of decidual spiral arteries, altered uterine artery function and led to fewer DBA+ uterine natural killer (uNK) cells, resulting in late gestation fetal loss and fetal growth restriction. Replacing the Treg cells by transfer from wild-type donors mitigated the impact on uNK cells, vascular remodeling, and fetal loss. RNA sequencing of decidua revealed genes associated with NK cell function and placental extravillous trophoblasts were dysregulated after Treg cell depletion, and normalized by Treg cell replacement. These data implicate Treg cells as essential upstream drivers of uterine vascular adaptation to pregnancy, through a mechanism likely involving phenotypic regulation of uNK cells and trophoblast invasion. The findings provide insight into mechanisms linking impaired adaptive immune tolerance and altered spiral artery remodeling, two hallmark features of preeclampsia.
Authors
Shanna L. Hosking, Lachlan M. Moldenhauer, Ha M. Tran, Hon Y. Chan, Holly M. Groome, Evangeline A.K. Lovell, Ella S. Green, Stephanie E. O'Hara, Claire T. Roberts, Kerrie L. Foyle, Sandra T. Davidge, Sarah A. Robertson, Alison S. Care
Abstract
Peptidoglycans (PGNs) are structural polymers of the bacterial cell wall and a common microbial molecular pattern encountered by our immune system daily. Low levels of PGNs are constitutively present in the systemic circulation in humans and elevate during inflammatory pathologies. Since all known PGN sensors are intracellular, PGN internalization is a prerequisite for the initiation of cellular immune responses. Here we report the mechanisms controlling the recognition and uptake of polymeric PGNs by circulating human mononuclear phagocytes. We found that complement C3 and C4 opsonins govern PGN recognition and internalization, but no single opsonin is indispensable due to multiple uptake redundancies. We observed a bimodal internalization of polymeric PGNs with distinct requirements for complement C4. At low PGN concentrations, C3 mediated PGN recognition by surface receptors while the efficient internalization of PGN polymers critically required C4. Supraphysiologic PGN concentrations triggered a secondary uptake modality that was insensitive to C4 and mediated instead by C3 engagement of complement receptors 1 and 3. To our knowledge this is the first description of non-overlapping C3 and C4 opsonophagocytoses working in parallel. Controlling these uptake mechanisms has the potential to modulate PGN clearance and/or the dysregulated immune responses during bacterial infections.
Authors
Narcis I. Popescu, Jędrzej Kluza, Megan A. Reidy, Elizabeth Duggan, John D. Lambris, Linda F. Thompson, K. Mark Coggeshall
Abstract
Soft tissue trauma can cause immune system disturbance and neuropathological invasion, resulting in heterotopic ossification (HO) due to aberrant chondrogenic differentiation of mesenchymal stem cells (MSCs). However, the molecular mechanisms behind the interaction between the immune and nervous systems in promoting HO pathogenesis are unclear. In this study, we found that mast cell-specific deletion attenuated localized tissue inflammation, with marked inhibition of HO endochondral osteogenesis. Likewise, blockage of nerve growth factor (NGF) receptor, known as tropomyosin receptor kinase A (TrkA), led to similar attenuations in tissue inflammation and HO. Moreover, while NGF-TrkA signaling did not directly affect MSCs chondrogenic differentiation, it modulated mast cell activation in traumatic soft tissue. Mechanistically, lipid A in lipopolysaccharide binding to TrkA enhanced NGF-induced TrkA phosphorylation, synergistically stimulating mast cells to release neurotrophin-3 (NT3), thereby promoting MSCs chondrogenic differentiation in situ. Finally, analysis of single-cell datasets and human pathological specimens confirmed the important role of mast cell-mediated neuroinflammation in HO pathogenesis. In conclusion, NGF regulates mast cells in soft tissue trauma, and drives HO progression via paracrine NT3. Targeted early inhibition of mast cells holds substantial promise for treating traumatic HO.
Authors
Tao Jiang, Xiang Ao, Xin Xiang, Jie Zhang, Jieyi Cai, Jiaming Fu, Wensheng Zhang, Zhenyu Zheng, Jun Chu, Minjun Huang, Zhongmin Zhang, Liang Wang
Abstract
Urinary neutrophils are a hallmark of urinary tract infection (UTI), yet the mechanisms governing their activation, function, and efficacy in controlling infection remain incompletely understood. Tamm-Horsfall glycoprotein (THP), the most abundant protein in urine, uses terminal sialic acids to bind an inhibitory receptor and dampen neutrophil inflammatory responses. We hypothesized that neutrophil modulation is an integral part of THP-mediated host protection. In a UTI model, THP-deficient mice showed elevated urinary tract bacterial burdens, increased neutrophil recruitment, and more severe tissue histopathological changes compared to WT mice. Furthermore, THP-deficient mice displayed impaired urinary NETosis during UTI. To investigate the impact of THP on NETosis, we coupled in vitro fluorescence-based NET assays, proteomic analyses, and standard and imaging flow cytometry with peripheral human neutrophils. We found that THP increases proteins involved in respiratory chain, neutrophil granules, and chromatin remodeling pathways, enhances NETosis in an ROS-dependent manner, and drives NET-associated morphologic features including nuclear decondensation. These effects were observed only in the presence of a NETosis stimulus and could not be solely replicated with equivalent levels of sialic acid alone. We conclude that THP is a critical regulator of NETosis in the urinary tract, playing a key role in host defense against UTI.
Authors
Vicki Mercado-Evans, Holly Branthoover, Claude Chew, Camille Serchejian, Alexander B. Saltzman, Marlyd E. Mejia, Jacob J. Zulk, Ingrid Cornax, Victor Nizet, Kathryn A. Patras
Abstract
The cytokine interleukin-18 (IL-18) has immunostimulatory effects but is negatively regulated by a secreted binding protein, IL-18BP, that limits IL-18’s anti-cancer efficacy. A “decoy-resistant” form of IL-18 (DR-18), that avoids sequestration by IL-18BP while maintaining its immunostimulatory potential, has recently been developed. Here, we investigated the therapeutic potential of DR-18 in renal cell carcinoma (RCC). Using pan-tumor transcriptomic data, we found that clear cell RCC had among the highest expression of IL-18 receptor subunits and IL18BP of tumor types in the database. In samples from RCC patients treated with immune checkpoint inhibitors, IL-18BP protein expression increased in the tumor microenvironment and circulating in plasma in non-responding patients and decreased in the majority of responding patients. We used immunocompetent RCC murine models to assess the efficacy of DR-18 in combination with single- and dual-agent anti-PD-1 and anti-CTLA-4. In contrast to preclinical models of other tumor types, in RCC models DR-18 enhanced the activity of anti-CTLA-4 but not anti-PD-1 treatment. This activity correlated with intra-tumoral enrichment and clonal expansion of effector CD8+ T cells, decreased regulatory T cell levels, and enrichment of pro-inflammatory, anti-tumor myeloid cell populations. Our findings support further clinical investigation of the combination of DR-18 and anti-CTLA-4 in RCC.
Authors
David A. Schoenfeld, Dijana Djureinovic, David G. Su, Lin Zhang, Benjamin Y. Lu, Larisa Kamga, Jacqueline E. Mann, John D. Huck, Michael Hurwitz, David A. Braun, Lucia Jilaveanu, Aaron M. Ring, Harriet M. Kluger
Abstract
CD4+ T helper 1 (TH1) cells coordinate adaptive immune responses to intracellular pathogens, including viruses. Key to this function is the ability of TH1 cells to migrate within secondary lymphoid tissues, as well as to sites of inflammation, which relies on signals received through the chemokine receptor CXCR3. CXCR3 expression is driven by the TH1 lineage-defining transcription factor T-bet, and the cytokine-responsive Signal Transducer and Activator of Transcription (STAT) family members STAT1 and STAT4. Here, we identify the Ikaros zinc finger (IkZF) transcription factor Aiolos (Ikzf3) as an additional positive regulator of CXCR3 both in vitro and in vivo using a murine model of influenza virus infection. Mechanistically, we find that Aiolos-deficient CD4+ T cells exhibit decreased expression of key components of the IFNγ/STAT1 signaling pathway, including JAK2 and STAT1. Consequently, Aiolos deficiency results in decreased levels of STAT1 tyrosine phosphorylation and reduced STAT1 enrichment at the Cxcr3 promoter. We further find that Aiolos and STAT1 form a positive feedback loop via reciprocal regulation of each other downstream of IFNγ signaling. Collectively, our study demonstrates that Aiolos promotes CXCR3 expression on TH1 cells by propagating the IFNγ/STAT1 cytokine signaling pathway.
Authors
Melissa R. Leonard, Devin M. Jones, Kaitlin A. Read, Srijana Pokhrel, Jasmine A. Tuazon, Robert T. Warren, Jacob S. Yount, Kenneth J. Oestreich
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