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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 163 records · Page 9
All sourcesNASA NTRSDOE OSTI
DOE OSTI2019

Role of α-Fetoprotein in Regulation of Proliferation and Functional Activity of Naïve T Cells and Immune Memory T Cells

We studied the role of native α-fetoprotein preparation in the regulation of proliferation and functional activity of naïve T cells and immune memory T cells in vitro. The study was carried out on separated fractions of naïve T cells (CD45RA{sup +}) and immune memory T cells (CD45R0{sup +}) incubated with α-fetoprotein under conditions of TCR activation. At the level of naïve T cells, α-fetoprotein in a concentration of 100 U/ml reduced the expression of CD28, but increased the expression of CD25, while at the level of immune memory T cells α-fetoprotein (50 and 100 U/ml) only suppressed the expression of CD25. No effects of α-fetoprotein on the proliferative status of the studied lymphocyte subpopulations and on the expression of CD71 (proliferation marker) by these cells were detected. Addition of α-fetoprotein in a concentration of 100 U/ml increased the level of IL-2 in naïve T cell culture supernatants, while production of IL-2 by memory T cells remained unchanged. These data demonstrated the priority aspects of regulation of the functional activities of naïve T cells and immune memory T cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Clinical significance of soluble forms of immune checkpoint molecules in advanced esophageal cancer

Immune checkpoint molecules are expressed on cancer cells and regulate tumor immunity by binding to ligands on immune cells. Although soluble forms of immune checkpoint molecules have been detected in the blood of patients with some types of tumors, their roles have not been fully elucidated. Soluble PD-L1, PD-1, CD155, LAG3, and CD226 (sPD-L1, sPD-1, sCD155, sLAG3, and sCD226, respectively) were measured in the sera of 47 patients with advanced esophageal cancer and compared with those of 24 control subjects. Pretreatment levels of sPD-1 and sCD155 were significantly higher in the patients with cancer than in the control subjects (P = 0.023, P = 0.001). The sPD-1 levels tended to be higher in the patients with lymph node metastasis, a large tumor diameter, and higher levels of serum SCC antigen (P = 0.150, P = 0.189, and P = 0.078, respectively). However, higher levels of sCD155 were associated with a better response to chemotherapy and favorable overall survival (P = 0.111 and P = 0.068, respectively). After 2 courses of chemotherapy, the levels of sCD155 and sCD226 were significantly increased (P < 0.001 and P = 0.002, respectively). Moreover, the increase in sCD226 during chemotherapy was associated with poor treatment response (P = 0.019). sPD-1 levels are possibly dependent on the tumor aggressiveness of the esophageal cancer. Furthermore, the pretreatment levels of sCD155 and kinetic change of sCD226 after chemotherapy may be used as biomarkers of the treatment response and prognosis in patients with esophageal cancer.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

MicroRNA expression profiling provides novel insights into immune-related pathways involved in gastric cancer

Gastric cancer is one of the most common cancers, and an increasing number of studies have found that microRNAs (miRNAs) play essential roles in gastric cancer progression; however, the roles of specific miRNAs involved in the immune response to this disease remain unclear. We compared the miRNA expression in tissues from primary gastric cancer patients and healthy controls to find miRNAs dysregulated in gastric cancer and used bioinformatics tools to determine potential roles of these miRNAs in the immune system. We evaluated 25 primary gastric cancer tissues and five healthy gastric tissues. Quantitative real-time polymerase chain reaction was performed for a set of miRNAs, followed by the prediction of their target genes and functional enrichment analysis of these targets. Analysis of a microarray dataset showed that the miRNA miR-196a-5p was significantly upregulated, while miR-374a-5p and miR-375 were downregulated in gastric cancer patients. In addition, miR-374-5p was significantly downregulated in patients with metastasis compared with its expression levels in non-metastatic patients (p = 0.03). Bioinformatics analysis suggested that the pathways regulated by these differentially expressed miRNAs were related to the immune response, cell adhesion, and cell migration. Most importantly, this study provides a new insight into the potential use of multiple miRNAs to find distinct pathways of immune regulation in gastric cancer.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

Development of cell-based assay for predictively evaluating the FcγR-mediated human immune cell activation by therapeutic monoclonal antibodies

Therapeutic monoclonal antibodies (mAbs) have important roles in treatments for various cancers and inflammatory diseases. Their highly target specificities provide controlled safety profiles. However, therapeutic mAbs commonly pose a risk of the induction of the release of cytokines, which may result in adverse events including infusion reaction and cytokine release syndrome. Several mechanisms are involved in the cytokine releases induced by therapeutic mAbs, and the activation of immune effector cells via Fcγ receptors (FcγRs) is one of the putative mechanisms for most IgG-subclass mAbs. The relationship between cytokine releases and mAbs' Fc functions is not fully understood. Here we developed a simple reporter cell-based assay for estimating the FcγR-mediated activation of human immune effector cells by mAbs. Our use of the cell-based assay to compare Fc-engineered mAbs with different FcγR-activation profiles revealed that the releases of inflammatory cytokines and chemokines from human peripheral blood mononuclear cells (hPBMCs) induced by the mAbs were elevated by treatment with Fc-engineered mAbs with higher FcγR-activation properties. Our results also suggested the involvement of monocytic effector cells in the activation of hPBMCs as sources of released cytokines and chemokines, which may lead to the immune cell-mediated adverse events. Our new reporter cell assay is a promising tool for evaluating and predicting the activation of human immune cells by novel Fc-engineered mAbs. - Highlights: • A simple reporter assay for estimating the FcγR activation by mAbs is developed. • mAbs with higher FcγR-activation properties strongly activate hPBMC. • Monocytic effector cells are involved in the activation of hPBMCs by mAbs. • The reporter assay is useful for predicting the FcγR-mediated responses of hPBMCs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Effects of the RNA-binding protein, KSRP, on innate immune response against Helicobacter pylori infection in mice

Highlights: • H. pylori infection decreased expression of KSRP. • KSRP overexpression triggered HMOX1 and CXCL-2 ectopic expression. • KSRP overexpression facilitated H. pylori proliferation and colonization. • KSRP overexpression triggered more severe gastric mucosal damage. Helicobacter pylori (H. pylori) contributes to various gastric diseases such as chronic gastritis, gastric ulcer, and gastric carcinoma. Host innate immune response against the pathogen plays a significant role in elimination of pathogen infection. Importantly, pathogen elimination is closely related to numerous inflammatory-related genes that participate in complex biological response of cells to harmful stimuli. Here we studied effects of the KH-type splicing regulatory protein (KSRP), a RNA-binding protein, on innate immune response against H. pylori infection. We found that H. pylori infection downregulated KSRP expression directly, and that KSRP overexpression repressed upregulation of CXCL-2 expression induced by H. pylori and facilitated H. pylori proliferation in vitro. Similarly, KSRP overexpression in H. pylori mice also facilitated H. pylori proliferation and colonization, and induced more severe gastric mucosal damage. Intriguingly, CXCL-2 and HMOX-1 were upregulated in H. pylori infected mice after KSRP overexpression. This difference in expression of these genes implicated that KSRP was closely associated with and directly participated in the innate immune response against H. pylori. These results were beneficial for understanding the in vivo function of KSRP on innate immune response against pathogen infection.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The level of decoy epitope in PCV2 vaccine affects the neutralizing activity of sera in the immunized animals

Highlights: • We generated a novel antibody specific to an immunodominant decoy epitope of PCV2. • Using this novel antibody, we measured levels of decoy epitope in PCV2 vaccine. • Decoy epitope in PCV2 vaccine affected the neutralizing antibody titer induction. Viral pathogens have evolved a wide range of tactics to evade host immune responses and thus propagate effectively. One efficient tactic is to divert host immune responses toward an immunodominant decoy epitope and to induce non-neutralizing antibodies toward this epitope. Therefore, it is expected that the amount of decoy epitope in a subunit vaccine can affect the level of neutralizing antibody in an immunized animal. In this study, we tested this hypothesis by generating an antibody specific to the decoy epitope on the capsid protein of porcine circovirus type 2 (PCV2). Using this antibody, we found that two commercial vaccines contained statistically different amounts of the decoy epitope. The vaccine with lower levels of decoy epitope induced a significantly higher level of neutralizing antibody after immunization. This antibody can be used as an analytical tool to monitor the quality of a vaccine from batch to batch.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Stabilization of HDAC1 via TCL1-pAKT-CHFR axis is a key element for NANOG-mediated multi-resistance and stem-like phenotype in immune-edited tumor cells

Highlights: • NANOG contributes to stabilization of HDAC1 protein through AKT signaling pathway. • NANOG-AKT axis leads to phosphor-dependent inactivation of CHFR, which is an E3 ligase for HDAC1 protein. • HDAC1 confers immune-resistance, drug-resistance and stem-like phenotype through its catalytic activity. • AKT inhibition disrupts HDAC1-mediated multi-resistance and stem-like phenotype. Cancer immunoediting enriches NANOG expression in tumor cells, resulting in multi-drug resistance and stem-like phenotypes. We previously demonstrated that these NANOG-associated phenotypes are promoted through HDAC1 transcriptional upregulation. In this study, we identified that NANOG also contributes to the stabilization of HDAC1 protein through the AKT signaling pathway. NANOG-AKT axis leads to phosphor-dependent inactivation of CHFR, an E3 ligase for HDAC1 protein, and thereby inhibiting the ubiquitin-mediated degradation of HDAC1. Furthermore, AKT inhibition disrupts HDAC1 WT-mediated phenotypes but had no effect on the phenotypes mediated by HDAC1 FM, a mutant that is unable to interact with CHFR. Critically, we applied a catalytic dead mutant, HDAC1-H141A, to uncover that HDAC1 confers immune-resistance, drug-resistance and stem-like phenotype in tumor cells through its catalytic activity. Collectively, our results establish a firm molecular link in immune-edited tumor cells among NANOG, AKT, CHFR, and HDAC1, identifying HDAC1 as a molecular target in controlling NANOGHIGH immune-refractory cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Single-walled carbon nanotubes disturbed the immune and metabolic regulation function 13-weeks after a single intratracheal instillation

Due to their unique physicochemical properties, the potential health effects of single-walled carbon nanotubes (SWCNTs) have attracted continuous attention together with their extensive application. In this study, we aimed to identify local and systemic health effects following pulmonary persistence of SWCNTs. As expected, SWCNTs remained in the lung for 13 weeks after a single intratracheal instillation (50, 100, and 200 μg/kg). In the lung, the total number of cells and the percentages of lymphocytes and neutrophils significantly increased at 200 μg/kg compared to the control, and the Th1-polarized immune response was induced accompanying enhanced expression of tissue damage-related genes and increased release of chemokines. Additionally, SWCNTs enhanced the expression of antigen presentation-related proteins on the surface of antigen-presenting cells, however, maturation of dendritic cells was inhibited by their persistence. As compared to the control, a significant increase in the percentage of neutrophils and a remarkable decrease of BUN and potassium level were observed in the blood of mice treated with the highest dose. This was accompanied by the down-regulation of the expression of antigen presentation-related proteins on splenocytes. Moreover, protein and glucose metabolism were disturbed with an up-regulation of fatty acid β-oxidation. Taken together, we conclude that SWCNTs may induce adverse health effects by disturbing immune and metabolic regulation functions in the body. Therefore, careful application of SWCNTs is necessary for the enforcement of safety in nano-industries. - Highlights: • We evaluated local and systemic health effects following persistence of SWCNTs. • SWCNTs remained in the lung for 13 weeks after a single intratracheal instillation. • Th1-polarized immune response was induced in the lung. • The expression of antigen presentation-related proteins was altered. • Immune and metabolic regulation function were disturbed.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Kinetics of Intratumoral Immune Cell Activation During Chemoradiation for Cervical Cancer

Radiation therapy has direct cytotoxic effects on tumor-infiltrating lymphocytes, but it also has immune stimulatory effects that increase immune cell infiltration. The dynamics of these competing effects on immune cells at the site of the tumor are poorly characterized during chemoradiation treatment (CRT) because of the difficulty of obtaining consecutive tumor biopsies. We used a minimally invasive cervical cytobrushing method to analyze the kinetics of intratumoral immune cell changes in patients with cervical cancer during CRT.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2023

Analysis of tumor-immune functional responses in a mathematical model of neoantigen cancer vaccines

Cancer neoantigen vaccines have emerged as a promising approach to stimulating the immune system to fight cancer. We propose a simple model including key elements of cancer-immune interactions and conduct a phase plane analysis to understand the immunological mechanisms of cancer neoantigen vaccines. Analytical results are obtained for two widely used functional forms that represent the killing rate of tumor cells by immune cells: the law of mass action (LMA) and the dePillis-Radunskaya Law (LPR). Using the LMA, our results reveal that a slowly growing tumor can escape the immune surveillance and that there is a unique periodic solution. The LPR offers richer dynamics, in which tumor elimination and uncontrolled tumor growth are both present. We show that tumor elimination requires sufficient number of initial activated T cells in relationship to the malignant cells, which lends support to using the neoantigen cancer vaccine as an adjuvant therapy after the primary tumor is surgically removed or treated using radiotherapy. We also derive a sufficient condition for uncontrolled tumor growth under the assumption of the LPR. Here, the juxtaposition of analyses with these two different choices for the killing rate function highlights their importance on model behavior and biological implications, by which we hope to spur further theoretical and experimental work to understand mechanisms underlying different functional forms for the killing rate.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Glutamine antagonist-mediated immune suppression decreases pathology but delays virus clearance in mice during nonfatal alphavirus encephalomyelitis

Infection of weanling C57BL/6 mice with the TE strain of Sindbis virus (SINV) causes nonfatal encephalomyelitis associated with hippocampal-based memory impairment that is partially prevented by treatment with 6-diazo-5-oxo-l-norleucine (DON), a glutamine antagonist (Potter et al., J Neurovirol 21:159, 2015). To determine the mechanism(s) of protection, lymph node and central nervous system (CNS) tissues from SINV-infected mice treated daily for 1 week with low (0.3 mg/kg) or high (0.6 mg/kg) dose DON were examined. DON treatment suppressed lymphocyte proliferation in cervical lymph nodes resulting in reduced CNS immune cell infiltration, inflammation, and cell death compared to untreated SINV-infected mice. Production of SINV-specific antibody and interferon-gamma were also impaired by DON treatment with a delay in virus clearance. Cessation of treatment allowed activation of the antiviral immune response and viral clearance, but revived CNS pathology, demonstrating the ability of the immune response to mediate both CNS damage and virus clearance. -- Highlights: • Treatment with glutamine antagonist DON protects mice from alphavirus encephalitis. • DON treatment suppresses the antiviral immune response in draining lymphoid tissue. • DON decreases inflammation and cell death in infected brain and spinal cord. • DON decreases production of antiviral antibody and IFN-γ and delays virus clearance. • With cessation of DON treatment, immunopathology and virus clearance appear.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

The effect of DNA damage on the pattern of immune-detectable DNA methylation in mouse embryonic fibroblasts

The methylation of cytosine at CpG dinucleotides (5meC) is an important epigenetic mechanism that governs genome stability and gene expression. Important ontological and pathological transitions are associated with marked global changes in detectable levels of methylation. We have previously found two pools of immune-detectable 5meC exist within cells, a pool that can be detected after acid treatment of fixed cells to denature chromatin and another large but variable pool that requires a further tryptic digestion step for complete epitope retrieval. The trypsin-sensitive pool has been shown to be largely associated with the heterochromatic fraction (by a heterochromatin marker, HP1-β) of the genome, and the size of this pool varies with the growth disposition of cells. Since DNA damage imposes large changes on chromatin structure the present study analyzed how such changes influences the faithful immunological detection of 5meC within mouse embryonic fibroblasts. DNA damage was induced by either UV-irradiation or doxorubicin treatment, each of which resulted in increased levels of immune-detectable 5meC at 24–48 h after treatment. There was a marked trypsin-sensitive pool of 5meC in these cells which was significantly increased after DNA damage. The increased levels of 5meC staining predominantly co-located with heterochromatic foci within nuclei, as assessed by HP1-β staining. The relative amount of masked 5meC after DNA damage was positively associated with increased levels of HP1-β. The methyl binding protein, MBD1, was a less reliable measure of changes in 5meC, with a significant fraction of 5meC not being marked by MBD1. The cyto-epigenetic approaches used here reveal dynamism in the levels and localization of immune-detectable 5meC within the nuclei of fibroblasts in response to DNA damage. - Highlights: • Immune-detectable 5meC within two pools retrieved after acid and trypsin after acid. • The size of the trypsin-sensitive pool varied in response to DNA damage. • This was associated with changes in the level of HP1-β within heterochromatic foci. • Epitope retrieval method detected remarkable dynamism in 5meC's level and location.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

DYNC1H1 regulates NSCLC cell growth and metastasis by IFN-γ-JAK-STAT signaling and is associated with an aberrant immune response

Highlights: • DYNC1H1 is upregulated and its high expression predicted poor outcomes in NSCLC. • Loss of function of DYNC1H1 inhibits cell growth and metastasis of NSCLC cells in vitro. • DYNC1H1 knockdown inhibited metastasis of NSCLC cells in vivo. • DYNC1H1 loss of function suppresses IFN-γ-JAK-STAT signaling pathway in NSCLC. • DYNC1H1 expression is correlated with aberrant immune response in NSCLC indicated by analysis of TCGA immune data. It is urgent to identify new biomarkers and therapeutic targets to ameliorate the clinical prognosis of patients with lung cancer. The functional significance and molecular mechanism of dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) in nonsmall cell lung cancer (NSCLC) progression is still elusive. In our current study, publicly available data and Western blotting experiments confirmed that DYNC1H1 expression was upregulated in lung cancer samples compared with noncancerous samples. Quantitative real-time PCR (qPCR) results indicated that high DYNC1H1 expression in lung cancer tissues was significantly associated with clinical tumor stage and distal metastasis; moreover, its high expression was negatively correlated with prognosis. Functional experiments demonstrated that DYNC1H1 loss of function caused a significant decrease in cell viability and cell proliferative ability, inhibition of the cell cycle, and promotion of both migration potential and invasion potential in vitro. Animal experiments by tail vein injection of lung cancer cells showed that DYNC1H1 knockdown significantly decreased lung cancer metastasis. Mechanistically, the results from a human protein array showed changes in the IFN-γ-JAK-STAT signaling pathway, and analysis of The Cancer Genome Atlas (TCGA) immune data demonstrated that disturbance of the immune microenvironment might be involved in the impaired growth and metastatic ability mediated by DYNC1H1 loss in NSCLC. DYNC1H1 might serve as a promising biological marker of prognosis and a potential clinical therapeutic target for patients with NSCLC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Phage-specific immunity impairs efficacy of bacteriophage targeting Vancomycin Resistant Enterococcus in a murine model

Bacteriophage therapy is a promising approach to address antimicrobial infections though questions remain regarding the impact of the immune response on clinical effectiveness. Here, we develop a mouse model to assess phage treatment using a cocktail of five phages from the Myoviridae and Siphoviridae families that target Vancomycin-Resistant Enterococcus gut colonization. Phage treatment significantly reduces fecal bacterial loads of Vancomycin-Resistant Enterococcus. We also characterize immune responses elicited following administration of the phage cocktail. While minimal innate responses are observed after phage administration, two rounds of treatment induces phage-specific neutralizing antibodies and accelerate phage clearance from tissues. Interestingly, the myophages in our cocktail induce a more robust neutralizing antibody response than the siphophages. This anti-phage immunity reduces the effectiveness of the phage cocktail in our murine model. Collectively, this study shows phage-specific immune responses may be an important consideration in the development of phage cocktails for therapeutic use.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

A TLR7-nanoparticle adjuvant promotes a broad immune response against heterologous strains of influenza and SARS-CoV-2

The ideal vaccine against viruses such as influenza and SARS-CoV-2 must provide a robust, durable and broad immune protection against multiple viral variants. However, antibody responses to current vaccines often lack robust cross-reactivity. Here we describe a polymeric Toll-like receptor 7 agonist nanoparticle (TLR7-NP) adjuvant, which enhances lymph node targeting, and leads to persistent activation of immune cells and broad immune responses. When mixed with alum-adsorbed antigens, this TLR7-NP adjuvant elicits cross-reactive antibodies for both dominant and subdominant epitopes and antigen-specific CD8 + T-cell responses in mice. This TLR7-NP-adjuvanted influenza subunit vaccine successfully protects mice against viral challenge of a different strain. This strategy also enhances the antibody response to a SARS-CoV-2 subunit vaccine against multiple viral variants that have emerged. Moreover, this TLR7-NP augments antigen-specific responses in human tonsil organoids. Overall, we describe a nanoparticle adjuvant to improve immune responses to viral antigens, with promising implications for developing broadly protective vaccines.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

A miniature CRISPR–Cas10 enzyme confers immunity by inhibitory signalling

Microbial and viral co-evolution has created immunity mechanisms involving oligonucleotide signalling that share mechanistic features with human antiviral systems1. In these pathways, including cyclic oligonucleotide-based antiphage signalling systems (CBASSs) and type III CRISPR systems in bacteria and cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) in humans, oligonucleotide synthesis occurs upon detection of virus or foreign genetic material in the cell, triggering the antiviral response2, 3–4. Here, in an unexpected inversion of this process, we show that the CRISPR-related enzyme mCpol synthesizes cyclic oligonucleotides constitutively as part of an active mechanism that represses a toxic effector. Cell-based experiments demonstrated that the absence or loss of mCpol-produced cyclic oligonucleotides triggers cell death, preventing the spread of viruses that attempt immune evasion by depleting host cyclic nucleotides. Structural and mechanistic investigation revealed mCpol to be a di-adenylate cyclase whose product, c-di-AMP, prevents toxic oligomerization of the effector protein 2TMβ. Analysis of cells by fluorescence microscopy showed that lack of mCpol allows 2TMβ-mediated cell death due to inner membrane collapse. These findings unveil a powerful defence strategy against virus-mediated immune suppression, expanding our understanding of the role of oligonucleotides in immunity.

Doherty, Erin E↗
DOE OSTI2024

Structural basis for the activity and specificity of the immune checkpoint inhibitor lirilumab

The clinical success of immune checkpoint inhibitors has underscored the key role of the immune system in controlling cancer. Current FDA-approved immune checkpoint inhibitors target the regulatory receptor pathways of cytotoxic T-cells to enhance their anticancer responses. Despite an abundance of evidence that natural killer (NK) cells can also mediate potent anticancer activities, there are no FDA-approved inhibitors targeting NK cell specific checkpoint pathways. Lirilumab, the most clinically advanced NK cell checkpoint inhibitor, targets inhibitory killer immunoglobulin-like receptors (KIRs), however it has yet to conclusively demonstrate clinical efficacy. Here we describe the crystal structure of lirilumab in complex with the inhibitory KIR2DL3, revealing the precise epitope of lirilumab and the molecular mechanisms underlying KIR checkpoint blockade. Notably, the epitope includes several key amino acids that vary across the human population, and binding studies demonstrate the importance of these amino acids for lirilumab binding. These studies reveal how KIR variations in patients could influence the clinical efficacy of lirilumab and reveal general concepts for the development of immune checkpoint inhibitors targeting NK cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Analysis of intraspecies diversity reveals a subset of highly variable plant immune receptors and predicts their binding sites

The evolution of recognition specificities by the immune system depends on the generation of receptor diversity and on connecting the binding of new antigens with the initiation of downstream signaling. In plant immunity, the innate Nucleotide-Binding Leucine-Rich Repeat (NLR) receptor family enables antigen binding and immune signaling. In this study, we surveyed the NLR complements of 62 ecotypes of Arabidopsis thaliana and 54 lines of Brachypodium distachyon and identified a limited number of NLR subfamilies that show high allelic diversity. We show that the predicted specificity-determining residues cluster on the surfaces of Leucine-Rich Repeat domains, but the locations of the clusters vary among NLR subfamilies. By comparing NLR phylogeny, allelic diversity, and known functions of the Arabidopsis NLRs, we formulate a hypothesis for the emergence of direct and indirect pathogen-sensing receptors and of the autoimmune NLRs. These findings reveal the recurring patterns of evolution of innate immunity and can inform NLR engineering efforts.

59 BASIC BIOLOGICAL SCIENCES↗