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1.
Immunity ; 56(10): 2358-2372.e5, 2023 10 10.
Article in English | MEDLINE | ID: mdl-37699392

ABSTRACT

Lung-resident memory B cells (lung-BRMs) differentiate into plasma cells after reinfection, providing enhanced pulmonary protection. Here, we investigated the determinants of lung-BRM differentiation upon influenza infection. Kinetic analyses revealed that influenza nucleoprotein (NP)-specific BRMs preferentially differentiated early after infection and required T follicular helper (Tfh) cell help. BRM differentiation temporally coincided with transient interferon (IFN)-γ production by Tfh cells. Depletion of IFN-γ in Tfh cells prevented lung-BRM differentiation and impaired protection against heterosubtypic infection. IFN-γ was required for expression of the transcription factor T-bet by germinal center (GC) B cells, which promoted differentiation of a CXCR3+ GC B cell subset that were precursors of lung-BRMs and CXCR3+ memory B cells in the mediastinal lymph node. Absence of IFN-γ signaling or T-bet in GC B cells prevented CXCR3+ pre-memory precursor development and hampered CXCR3+ memory B cell differentiation and subsequent lung-BRM responses. Thus, Tfh-cell-derived IFN-γ is critical for lung-BRM development and pulmonary immunity, with implications for vaccination strategies targeting BRMs.


Subject(s)
Influenza, Human , T-Lymphocytes, Helper-Inducer , Humans , Interferon-gamma/metabolism , Memory B Cells , T Follicular Helper Cells/metabolism , Germinal Center , Cell Differentiation , Receptors, CXCR3/metabolism
2.
Immunity ; 56(4): 847-863.e8, 2023 04 11.
Article in English | MEDLINE | ID: mdl-36958335

ABSTRACT

Seasonal influenza vaccination elicits hemagglutinin (HA)-specific memory B (Bmem) cells, and although multiple Bmem cell populations have been characterized, considerable heterogeneity exists. We found that HA-specific human Bmem cells differed in the expression of surface marker FcRL5 and transcriptional factor T-bet. FcRL5+T-bet+ Bmem cells were transcriptionally similar to effector-like memory cells, while T-betnegFcRL5neg Bmem cells exhibited stem-like central memory properties. FcRL5+ Bmem cells did not express plasma-cell-commitment factors but did express transcriptional, epigenetic, metabolic, and functional programs that poised these cells for antibody production. Accordingly, HA+ T-bet+ Bmem cells at day 7 post-vaccination expressed intracellular immunoglobulin, and tonsil-derived FcRL5+ Bmem cells differentiated more rapidly into antibody-secreting cells (ASCs) in vitro. The T-bet+ Bmem cell response positively correlated with long-lived humoral immunity, and clonotypes from T-bet+ Bmem cells were represented in the secondary ASC response to repeat vaccination, suggesting that this effector-like population predicts influenza vaccine durability and recall potential.


Subject(s)
Influenza Vaccines , Influenza, Human , Humans , Influenza, Human/prevention & control , Antibody Formation , Memory B Cells , Vaccination , Immunologic Memory , Antibodies, Viral
3.
Immunity ; 55(3): 494-511.e11, 2022 03 08.
Article in English | MEDLINE | ID: mdl-35263568

ABSTRACT

Interleukin (IL)-22 is central to immune defense at barrier sites. We examined the contributions of innate lymphoid cell (ILC) and T cell-derived IL-22 during Citrobacter rodentium (C.r) infection using mice that both report Il22 expression and allow lineage-specific deletion. ILC-derived IL-22 activated STAT3 in C.r-colonized surface intestinal epithelial cells (IECs) but only temporally restrained bacterial growth. T cell-derived IL-22 induced a more robust and extensive activation of STAT3 in IECs, including IECs lining colonic crypts, and T cell-specific deficiency of IL-22 led to pathogen invasion of the crypts and increased mortality. This reflected a requirement for T cell-derived IL-22 for the expression of a host-protective transcriptomic program that included AMPs, neutrophil-recruiting chemokines, and mucin-related molecules, and it restricted IFNγ-induced proinflammatory genes. Our findings demonstrate spatiotemporal differences in the production and action of IL-22 by ILCs and T cells during infection and reveal an indispensable role for IL-22-producing T cells in the protection of the intestinal crypts.


Subject(s)
Citrobacter rodentium , Enterobacteriaceae Infections , Animals , Anti-Bacterial Agents , Immunity, Innate , Interleukins/metabolism , Intestinal Mucosa , Lymphocytes/metabolism , Mice , Mice, Inbred C57BL , T-Lymphocytes/metabolism , Interleukin-22
4.
Immunity ; 53(1): 172-186.e6, 2020 07 14.
Article in English | MEDLINE | ID: mdl-32610078

ABSTRACT

B-1 B cells derive from a developmental program distinct from that of conventional B cells, through B cell receptor (BCR)-dependent positive selection of fetally derived precursors. Here, we used direct labeling of B cells reactive with the N-acetyl-D-glucosamine (GlcNAc)-containing Lancefield group A carbohydrate of Streptococcus pyogenes to study the effects of bacterial antigens on the emergent B-1 B cell clonal repertoire. The number, phenotype, and BCR clonotypes of GlcNAc-reactive B-1 B cells were modulated by neonatal exposure to heat-killed S. pyogenes bacteria. GlcNAc-reactive B-1 clonotypes and serum antibodies were reduced in germ-free mice compared with conventionally raised mice. Colonization of germ-free mice with a conventional microbiota promoted GlcNAc-reactive B-1 B cell development and concomitantly elicited clonally related IgA+ plasma cells in the small intestine. Thus, exposure to microbial antigens in early life determines the clonality of the mature B-1 B cell repertoire and ensuing antibody responses, with implications for vaccination approaches and schedules.


Subject(s)
Antibodies, Bacterial/blood , Antigens, Bacterial/immunology , B-Lymphocyte Subsets/immunology , Polysaccharides, Bacterial/immunology , Streptococcus pyogenes/immunology , Acetylglucosamine/metabolism , Animals , Animals, Newborn/immunology , Germ-Free Life/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Microbiota/immunology
5.
Immunity ; 50(5): 1172-1187.e7, 2019 05 21.
Article in English | MEDLINE | ID: mdl-31076359

ABSTRACT

Although viral infections elicit robust interferon-γ (IFN-γ) and long-lived antibody-secreting cell (ASC) responses, the roles for IFN-γ and IFN-γ-induced transcription factors (TFs) in ASC development are unclear. We showed that B cell intrinsic expression of IFN-γR and the IFN-γ-induced TF T-bet were required for T-helper 1 cell-induced differentiation of B cells into ASCs. IFN-γR signaling induced Blimp1 expression in B cells but also initiated an inflammatory gene program that, if not restrained, prevented ASC formation. T-bet did not affect Blimp1 upregulation in IFN-γ-activated B cells but instead regulated chromatin accessibility within the Ifng and Ifngr2 loci and repressed the IFN-γ-induced inflammatory gene program. Consistent with this, B cell intrinsic T-bet was required for formation of long-lived ASCs and secondary ASCs following viral, but not nematode, infection. Therefore, T-bet facilitates differentiation of IFN-γ-activated inflammatory effector B cells into ASCs in the setting of IFN-γ-, but not IL-4-, induced inflammatory responses.


Subject(s)
B-Lymphocytes/immunology , Interferon-gamma/immunology , Receptors, Interferon/metabolism , T-Box Domain Proteins/metabolism , T-Lymphocytes, Helper-Inducer/immunology , Animals , Antibody-Producing Cells/immunology , B-Lymphocytes/cytology , Cell Differentiation/immunology , Cells, Cultured , Chromatin/metabolism , Influenza A Virus, H1N1 Subtype/immunology , Influenza A Virus, H3N2 Subtype/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Nematospiroides dubius/immunology , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/virology , Positive Regulatory Domain I-Binding Factor 1/biosynthesis , Strongylida Infections/immunology , Strongylida Infections/parasitology , T-Box Domain Proteins/genetics , Interferon gamma Receptor
6.
Nat Immunol ; 16(7): 755-65, 2015 Jul.
Article in English | MEDLINE | ID: mdl-26006014

ABSTRACT

Acute systemic lupus erythematosus (SLE) courses with surges of antibody-secreting cells (ASCs) whose origin, diversity and contribution to serum autoantibodies remain unknown. Here, deep sequencing, proteomic profiling of autoantibodies and single-cell analysis demonstrated highly diversified ASCs punctuated by clones expressing the variable heavy-chain region VH4-34 that produced dominant serum autoantibodies. A fraction of ASC clones contained autoantibodies without mutation, a finding consistent with differentiation outside the germinal centers. A substantial ASC segment was derived from a distinct subset of newly activated naive cells of considerable clonality that persisted in the circulation for several months. Thus, selection of SLE autoreactivities occurred during polyclonal activation, with prolonged recruitment of recently activated naive B cells. Our findings shed light on the pathogenesis of SLE, help explain the benefit of agents that target B cells and should facilitate the design of future therapies.


Subject(s)
Antibody Diversity/immunology , Antibody-Producing Cells/immunology , Autoantibodies/immunology , Cell Proliferation , Lupus Erythematosus, Systemic/immunology , Acute Disease , Amino Acid Sequence , Antibody Diversity/genetics , Antibody-Producing Cells/metabolism , Autoantibodies/genetics , Autoantibodies/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Base Sequence , Clone Cells/immunology , Clone Cells/metabolism , Flow Cytometry , Humans , Immunoglobulin G/blood , Immunoglobulin G/genetics , Immunoglobulin G/immunology , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Heavy Chains/immunology , Immunoglobulin Heavy Chains/metabolism , Immunoglobulin Variable Region/genetics , Immunoglobulin Variable Region/immunology , Immunoglobulin Variable Region/metabolism , Influenza Vaccines/immunology , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/metabolism , Molecular Sequence Data , Proteome/analysis , Proteome/immunology , Proteomics/methods , Sequence Homology, Amino Acid , Single-Cell Analysis/methods , Tandem Mass Spectrometry , Tetanus Toxoid/immunology
7.
Gastroenterology ; 2024 Aug 20.
Article in English | MEDLINE | ID: mdl-39173722

ABSTRACT

BACKGROUND AND AIMS: Inflammatory bowel disease is a chronic manifestation of dysregulated immune response to the gut microbiota in genetically pre-disposed hosts. Nearly half of patients with Crohn's disease (CD) develop selective serum IgG response to flagellin proteins expressed by bacteria in the Lachnospiraceae family. This study aimed to identify the binding epitopes of these IgG antibodies and assess their relevance in CD and in homeostasis. METHODS: Sera from an adult CD cohort, a treatment-naïve pediatric CD cohort, and three independent non-IBD infant cohorts were analyzed using novel techniques including a flagellin peptide microarray and a flagellin peptide cytometric bead array. RESULTS: A dominant B cell peptide epitope in CD patients was identified, locating in the highly conserved "hinge region" between the D0 and D1 domains at the amino-terminus of Lachnospiraceae flagellins. Elevated serum IgG reactivity to the hinge peptide was strongly associated with incidence of CD and the development of disease complications in children with CD up to five years in advance. Notably, high levels of serum IgG to the hinge epitope were also found in most infants from 3 different geographic regions (Uganda, Sweden, and the USA) at one year of age, which decrements rapidly afterwards. CONCLUSIONS: These findings identified a distinct subset of CD patients, united by a shared reactivity to a dominant commensal bacterial flagellin epitope that may represent failure of a homeostatic response to the gut microbiota beginning in infancy.

8.
Nat Immunol ; 14(9): 949-58, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23933892

ABSTRACT

Leukocytes must traverse inflamed tissues to effectively control local infection. Although motility in dense tissues seems to be integrin independent and based on actomyosin-mediated protrusion and contraction, during inflammation, changes to the extracellular matrix (ECM) may necessitate distinct motility requirements. Indeed, we found that the interstitial motility of T cells was critically dependent on Arg-Gly-Asp (RGD)-binding integrins in the inflamed dermis. Inflammation-induced deposition of fibronectin was functionally linked to higher expression of integrin αV on effector CD4⁺ T cells. By intravital multiphoton imaging, we found that the motility of CD4⁺ T cells was dependent on αV expression. Selective blockade or knockdown of αV arrested T helper type 1 (TH1) cells in the inflamed tissue and attenuated local effector function. Our data demonstrate context-dependent specificity of lymphocyte movement in inflamed tissues that is essential for protective immunity.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cell Movement/immunology , Inflammation/immunology , Inflammation/metabolism , Integrin alphaV/metabolism , Animals , Dermis/immunology , Dermis/metabolism , Extracellular Matrix/metabolism , Gene Expression Regulation , Inflammation/genetics , Integrin alphaV/genetics , Lymph Nodes/immunology , Mice , Oligopeptides/metabolism , Protein Binding , Th1 Cells/immunology , Th1 Cells/metabolism
9.
Immunity ; 43(1): 132-45, 2015 Jul 21.
Article in English | MEDLINE | ID: mdl-26187412

ABSTRACT

Antibody responses to viral infections are sustained for decades by long-lived plasma cells (LLPCs). However, LLPCs have yet to be characterized in humans. Here we used CD19, CD38, and CD138 to identify four PC subsets in human bone marrow (BM). We found that the CD19(-)CD38(hi)CD138(+) subset was morphologically distinct, differentially expressed PC-associated genes, and exclusively contained PCs specific for viral antigens to which the subjects had not been exposed for more than 40 years. Protein sequences of measles- and mumps-specific circulating antibodies were encoded for by CD19(-)CD38(hi)CD138(+) PCs in the BM. Finally, we found that CD19(-)CD38(hi)CD138(+) PCs had a distinct RNA transcriptome signature and human immunoglobulin heavy chain (VH) repertoire that was relatively uncoupled from other BM PC subsets and probably represents the B cell response's "historical record" of antigenic exposure. Thus, our studies define human LLPCs and provide a mechanism for the life-long maintenance of anti-viral antibodies in the serum.


Subject(s)
Antibodies, Viral/immunology , Bone Marrow Cells/immunology , Measles virus/immunology , Mumps virus/immunology , Plasma Cells/immunology , ADP-ribosyl Cyclase 1/metabolism , Adult , Aged , Antibodies, Viral/blood , Antigens, CD19/metabolism , Humans , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Heavy Chains/immunology , Membrane Glycoproteins/metabolism , Middle Aged , RNA, Messenger/genetics , Syndecan-1/metabolism , Young Adult
10.
Gastroenterology ; 161(2): 522-535.e6, 2021 08.
Article in English | MEDLINE | ID: mdl-33844987

ABSTRACT

BACKGROUND AND AIMS: Crohn's disease and ulcerative colitis are characterized by dysregulated adaptive immune responses to the microbiota in genetically susceptible individuals, but the specificity of these responses remains largely undefined. Therefore, we developed a microbiota antigen microarray to characterize microbial antibody reactivity, particularly to human-derived microbiota flagellins, in inflammatory bowel disease. METHODS: Sera from healthy volunteers (n = 87) at the University of Alabama at Birmingham and from patients recruited from the Kirklin Clinic of University of Alabama at Birmingham Hospital, including patients with Crohn's disease (n = 152) and ulcerative colitis (n = 170), were individually probed against microbiota bacterial flagellins of both mouse and human origin and analyzed for IgG and IgA antibody responses. Circulating flagellin-reactive T effector (CD4+CD154+) and T regulatory (CD4+CD137+) cells were isolated and evaluated in selected patients. Resulting adaptive immune responses were compared with corresponding clinical data to determine relevancy to disease behavior. RESULTS: We show that patients with IBD express selective patterns of antibody reactivity to microbiota flagellins. Patients with Crohn's disease, but not patients with ulcerative colitis, display augmented serum IgG to human ileal-localized Lachnospiraceae flagellins, with a subset of patients having high responses to more than 10 flagellins. Elevated responses to CBir1, a mouse Lachnospiraceae flagellin used clinically to diagnose CD, correlated with multi-Lachnospiraceae flagellin reactivity. In this subset of patients with CD, multi-flagellin reactivity was associated with elevated flagellin-specific CD154+CD45RA- T memory cells, a reduced ratio of flagellin-reactive CD4+ T regulatory to T effector cells, and a high frequency of disease complications. CONCLUSIONS: Patients with Crohn's disease display strong adaptive immune response to human-derived Lachnospiraceae flagellins, which may be targeted for prognosis and future personalized therapies.


Subject(s)
Adaptive Immunity , Antibodies, Bacterial/blood , Antigens, Bacterial/immunology , CD4-Positive T-Lymphocytes/immunology , Clostridiales/immunology , Crohn Disease/immunology , Flagellin/immunology , Immunoglobulin G/blood , Adult , Aged , Aged, 80 and over , Antigens, Bacterial/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , B-Lymphocytes/microbiology , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/microbiology , Case-Control Studies , Clostridiales/metabolism , Colitis, Ulcerative/blood , Colitis, Ulcerative/immunology , Colitis, Ulcerative/microbiology , Crohn Disease/blood , Crohn Disease/microbiology , Cross-Sectional Studies , Female , Flagellin/metabolism , Humans , Immunoglobulin A/blood , Male , Middle Aged , Young Adult
11.
Immunol Rev ; 284(1): 120-131, 2018 07.
Article in English | MEDLINE | ID: mdl-29944759

ABSTRACT

Understanding antibody repertoires and in particular, the properties and fates of B cells expressing potentially pathogenic antibodies is critical to define the mechanisms underlying multiple immunological diseases including autoimmune and allergic conditions as well as transplant rejection. Moreover, an integrated knowledge of the antibody repertoires expressed by B cells and plasma cells (PC) of different functional properties and longevity is essential to develop new therapeutic strategies, better biomarkers for disease segmentation, and new assays to measure restoration of B-cell tolerance or, at least, of normal B-cell homeostasis. Reaching these goals, however, will require a more precise phenotypic, functional and molecular definition of B-cell and PC populations, and a comprehensive analysis of the antigenic reactivity of the antibodies they express. While traditionally hampered by technical and ethical limitations in human experimentation, new technological advances currently enable investigators to address these questions in a comprehensive fashion. In this review, we shall discuss these concepts as they apply to the study of Systemic Lupus Erythematosus.


Subject(s)
Autoantibodies/immunology , Autoimmunity/immunology , B-Lymphocytes/immunology , Immune Tolerance/immunology , Lupus Erythematosus, Systemic/immunology , Lymphocyte Activation/immunology , Humans , Lupus Erythematosus, Systemic/pathology
12.
Clin Orthop Relat Res ; 473(9): 2735-49, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26013151

ABSTRACT

BACKGROUND: Because immunity against Staphylococcus aureus has not been fully elucidated, there is no diagnostic test to gauge how robust a patient's host response is likely to be. Therefore, we aimed to develop a test for specific antibodies in serum with diagnostic and prognostic potential. QUESTIONS/PURPOSES: We describe the development and validation of a multiplex immunoassay for characterizing a patient's immune response against 14 known S aureus antigens, which we then used to answer four questions: (1) Do certain antigens predominate in the immune response against S aureus? (2) Is there a predominant pattern of antigens recognized by patients and mice with infections? (3) Is the immunoglobulin G (IgG) response to any single antigen a useful predictor of ongoing S aureus infection? (4) Does measurement of the combined response against all 14 antigens provide a better predictor of ongoing infection? METHODS: A case-control study was performed. Sera were collected from 35 consecutive patients with S aureus culture-confirmed (methicillin-sensitive S aureus or methicillin-resistant S aureus) musculoskeletal infections (deep implant-associated, osteomyelitis, and cases of established septic arthritis). Patients were excluded only if they did not give informed consent for participation. Twenty-four patients had implant infections after total joint replacements, five had fracture implant infections, four had native knee infections, and two had chronic osteomyelitis without an implant. Control patients were chosen from a group of healthy, medically optimized patients scheduled to undergo elective arthroplasty. Control patients were matched for age (± 3 years), BMI (± 3 kg/m(2)), and sex as closely as possible to patients with infections. Sera from patients with S aureus infections and murine S aureus tibial implant infections were used to evaluate a multiplex immunoassay for immunoglobulin titers against 14 recombinant S aureus antigens. All patients were treated with organism-targeted antibiotic therapy and appropriate, timely surgery. Treatment response was monitored with clinical examination, erythrocyte sedimentation rate, C-reactive protein, and resampling of the infection site for the pathogen as needed. Elevated inflammatory markers or persistent positive culture results were considered evidence of ongoing infection. Treatment provided was considered standard-of-care therapy in our medical center and all patients were treated jointly with a board-certified infectious disease specialist. RESULTS: Four antigens elicited more than 65% of the measurable IgG, the most dominant being against iron-regulated surface determinant protein B (IsdB). Patients with infections had different patterns of elevated IgG titers, so that no single titer was elevated in more than 50% of patients with infections (area under the curve [AUC] ≤ 0.80). Multivariate analysis of IgG titers yielded greater predictive power of S aureus infection (AUC = 0.896). Patients with infections who had high titers against IsdB (median of survivors, 7.28 [25%-75% range, 2.22-21.26] vs median of patients with infection-related death, 40.41 [25%-75% range, 23.57-51.37], difference of medians, 33.13; p = 0.043) and iron-regulated surface determinant protein A (IsdA) median of survivors, 2.21 [25%-75% range, 0.79-9.11] vs median of patients with infection-related death, 12.24 [25%-75% range, 8.85-15.95], difference of medians, 10.03; p = 0.043) were more likely to die from infections than those who did not have high titers of IsdB. CONCLUSIONS: Measurement of the host antibody response is a predictor of ongoing infection that may prove to have prognostic value. Future studies will seek to enlarge the patient population with infections to allow us to reduce the number of antigens required to achieve a stronger predictive power. CLINICAL RELEVANCE: Measurement of the immune response against S aureus with this diagnostic tool may help guide future studies on prophylaxis and therapy in an era of personalized medicine and pathogen-specific therapies.


Subject(s)
Antibodies, Bacterial/blood , Antigens, Bacterial/immunology , Immunoassay , Immunoglobulin G/blood , Osteomyelitis/diagnosis , Serologic Tests/methods , Staphylococcal Infections/diagnosis , Staphylococcus aureus/immunology , Aged , Animals , Anti-Bacterial Agents/therapeutic use , Biomarkers/blood , Case-Control Studies , Disease Models, Animal , Female , Host-Pathogen Interactions , Humans , Male , Methicillin-Resistant Staphylococcus aureus/immunology , Mice, Inbred BALB C , Mice, Inbred C57BL , Middle Aged , Osteomyelitis/blood , Osteomyelitis/drug therapy , Osteomyelitis/immunology , Osteomyelitis/microbiology , Predictive Value of Tests , Reproducibility of Results , Staphylococcal Infections/blood , Staphylococcal Infections/drug therapy , Staphylococcal Infections/immunology , Staphylococcal Infections/microbiology , Time Factors , Treatment Outcome
13.
Aging Cell ; 23(6): e14133, 2024 06.
Article in English | MEDLINE | ID: mdl-38459711

ABSTRACT

Chronic low-grade inflammation, particularly elevated tumor necrosis factor (TNF) levels, occurs due to advanced age and is associated with greater susceptibility to infection. One reason for this is age-dependent macrophage dysfunction (ADMD). Herein, we use the adoptive transfer of alveolar macrophages (AM) from aged mice into the airway of young mice to show that inherent age-related defects in AM were sufficient to increase the susceptibility to Streptococcus pneumoniae, a Gram-positive bacterium and the leading cause of community-acquired pneumonia. MAPK phosphorylation arrays using AM lysates from young and aged wild-type (WT) and TNF knockout (KO) mice revealed multilevel TNF-mediated suppression of kinase activity in aged mice. RNAseq analyses of AM validated the suppression of MAPK signaling as a consequence of TNF during aging. Two regulatory phosphatases that suppress MAPK signaling, Dusp1 and Ptprs, were confirmed to be upregulated with age and as a result of TNF exposure both ex vivo and in vitro. Dusp1 is known to be responsible for glucocorticoid-mediated immune suppression, and dexamethasone treatment increased Dusp1 and Ptprs expression in cells and recapitulated the ADMD phenotype. In young mice, treatment with dexamethasone increased the levels of Dusp1 and Ptprs and their susceptibility to infection. TNF-neutralizing antibody reduced Dusp1 and Ptprs levels in AM from aged mice and reduced pneumonia severity following bacterial challenge. We conclude that chronic exposure to TNF increases the expression of the glucocorticoid-associated MAPK signaling suppressors, Dusp1 and Ptprs, which inhibits AM activation and increases susceptibility to bacterial pneumonia in older adults.


Subject(s)
Glucocorticoids , Macrophages, Alveolar , Tumor Necrosis Factor-alpha , Animals , Mice , Aging , Disease Susceptibility , Dual Specificity Phosphatase 1/metabolism , Dual Specificity Phosphatase 1/genetics , Glucocorticoids/pharmacology , Macrophages, Alveolar/metabolism , Macrophages, Alveolar/immunology , Mice, Inbred C57BL , Mice, Knockout , Pneumonia/immunology , Streptococcus pneumoniae , Tumor Necrosis Factor-alpha/metabolism , Female
14.
Cells ; 13(12)2024 Jun 10.
Article in English | MEDLINE | ID: mdl-38920641

ABSTRACT

The opioid epidemic continues to be a major public health issue that includes millions of people who inject drugs (PWID). PWID have increased incidence of serious infections, including HIV as well as metabolic and inflammatory sequelae. We sought to discern the extent of systemic alterations in humoral immunity associated with injection drug use, including alterations in the plasma proteome and its regulation of B cell responsiveness. Comprehensive plasma proteomics analysis of HIV negative/hepatitis C negative individuals with a history of recent injection heroin use was performed using mass spectrometry and ELISA. The effects of plasma from PWID and healthy controls on the in vitro proliferation and transcriptional profile of B cell responses to stimulation were determined by flow cytometry and RNA-Seq. The plasma proteome of PWID was distinct from healthy control individuals, with numerous immune-related analytes significantly altered in PWID, including complement (C3, C5, C9), immunoglobulin (IgD, IgM, kappa light chain), and other inflammatory mediators (CXCL4, LPS binding protein, C-reactive protein). The plasma of PWID suppressed the in vitro proliferation of B cells. Transcriptome analysis indicated that PWID plasma treatment increased B cell receptor and CD40 signaling and shifted B cell differentiation from plasma cell-like toward germinal center B cell-like transcriptional profiles. These results indicate that the systemic inflammatory milieu is substantially altered in PWID and may impact their B cell responses.


Subject(s)
B-Lymphocytes , Humans , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Male , Adult , Female , Cell Proliferation/drug effects , Substance Abuse, Intravenous/blood , Proteome/metabolism , Middle Aged
15.
Cell Host Microbe ; 32(7): 1177-1191.e7, 2024 Jul 10.
Article in English | MEDLINE | ID: mdl-38942027

ABSTRACT

Gut microbiota influence anti-tumor immunity, often by producing immune-modulating metabolites. However, microbes consume a variety of metabolites that may also impact host immune responses. We show that tumors grow unchecked in the omenta of microbe-replete mice due to immunosuppressive Tregs. By contrast, omental tumors in germ-free, neomycin-treated mice or mice colonized with altered Schaedler's flora (ASF) are spontaneously eliminated by CD8+ T cells. These mice lack Proteobacteria capable of arginine catabolism, causing increases in serum arginine that activate the mammalian target of the rapamycin (mTOR) pathway in Tregs to reduce their suppressive capacity. Transfer of the Proteobacteria, Escherichia coli (E. coli), but not a mutant unable to catabolize arginine, to ASF mice reduces arginine levels, restores Treg suppression, and prevents tumor clearance. Supplementary arginine similarly decreases Treg suppressive capacity, increases CD8+ T cell effectiveness, and reduces tumor burden. Thus, microbial consumption of arginine alters anti-tumor immunity, offering potential therapeutic strategies for tumors in visceral adipose tissue.


Subject(s)
Arginine , CD8-Positive T-Lymphocytes , Gastrointestinal Microbiome , Mice, Inbred C57BL , Omentum , T-Lymphocytes, Regulatory , Animals , Arginine/metabolism , Mice , T-Lymphocytes, Regulatory/immunology , Gastrointestinal Microbiome/immunology , CD8-Positive T-Lymphocytes/immunology , Omentum/immunology , TOR Serine-Threonine Kinases/metabolism , Proteobacteria , Escherichia coli/immunology , Neoplasms/immunology , Female
16.
Nat Commun ; 15(1): 3140, 2024 Apr 11.
Article in English | MEDLINE | ID: mdl-38605083

ABSTRACT

Pig-to-human xenotransplantation is rapidly approaching the clinical arena; however, it is unclear which immunomodulatory regimens will effectively control human immune responses to pig xenografts. Here, we transplant a gene-edited pig kidney into a brain-dead human recipient on pharmacologic immunosuppression and study the human immune response to the xenograft using spatial transcriptomics and single-cell RNA sequencing. Human immune cells are uncommon in the porcine kidney cortex early after xenotransplantation and consist of primarily myeloid cells. Both the porcine resident macrophages and human infiltrating macrophages express genes consistent with an alternatively activated, anti-inflammatory phenotype. No significant infiltration of human B or T cells into the porcine kidney xenograft is detectable. Altogether, these findings provide proof of concept that conventional pharmacologic immunosuppression may be able to restrict infiltration of human immune cells into the xenograft early after compatible pig-to-human kidney xenotransplantation.


Subject(s)
Gene Editing , Kidney , Animals , Swine , Humans , Animals, Genetically Modified , Heterografts , Transplantation, Heterologous , Graft Rejection/genetics
17.
Blood ; 118(13): 3591-602, 2011 Sep 29.
Article in English | MEDLINE | ID: mdl-21821704

ABSTRACT

The follicular lymphoma (FL) T-cell microenvironment plays a critical role in the biology of this disease. We therefore determined the lineage, differentiation state, and functional potential of FL-infiltrating CD4(+) T-helper cells (T(H)) compared with reactive and normal lymph node (NLN) T(H) cells. Relative to NLNs, FL cells have decreased proportions of naive and central memory but increased proportions of effector memory T(H) cells. We further show differences in the distribution and anatomical localization of CXCR5(+) T(H) populations that, on the basis of transcription factor analysis, include both regulatory and follicular helper T cells. On Staphylococcus enterotoxin-B stimulation, which stimulates T cells through the T-cell receptor, requires no processing by APCs, and can overcome regulator T cell-mediated suppression, the proportion of uncommitted primed precursor cells, as well as T(H)2 and T(H)17 cells is higher in FL cells than in reactive lymph nodes or NLNs. However, the proportion of T(H)1 and polyfunctional T(H) cells (producing multiple cytokines simultaneously) is similar in FL cells and NLNs. These data suggest that, although T(H)-cell differentiation in FL is skewed compared with NLNs, FL T(H) cells should have the same intrinsic ability to elicit antitumor effector responses as NLN T(H) cells when tumor suppressive mechanisms are attenuated.


Subject(s)
Cell Differentiation/immunology , Lymph Nodes/immunology , Lymphocytes, Tumor-Infiltrating/physiology , Lymphoma, Follicular/immunology , T-Lymphocytes, Helper-Inducer/physiology , Cell Differentiation/genetics , Cluster Analysis , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Expression Profiling , Humans , Immunologic Memory/genetics , Immunologic Memory/physiology , Lymph Nodes/metabolism , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Lymphoma, Follicular/genetics , Lymphoma, Follicular/metabolism , Lymphoma, Follicular/pathology , Microarray Analysis , Proto-Oncogene Proteins c-bcl-6 , Receptors, CXCR5/genetics , Receptors, CXCR5/metabolism , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolism
18.
Cell Mol Immunol ; 20(6): 651-665, 2023 06.
Article in English | MEDLINE | ID: mdl-37046042

ABSTRACT

Defective interleukin-6 (IL-6) signaling has been associated with Th2 bias and elevated IgE levels. However, the underlying mechanism by which IL-6 prevents the development of Th2-driven diseases remains unknown. Using a model of house dust mite (HDM)-induced Th2 cell differentiation and allergic airway inflammation, we showed that IL-6 signaling in allergen-specific T cells was required to prevent Th2 cell differentiation and the subsequent IgE response and allergic inflammation. Th2 cell lineage commitment required strong sustained IL-2 signaling. We found that IL-6 turned off IL-2 signaling during early T-cell activation and thus inhibited Th2 priming. Mechanistically, IL-6-driven inhibition of IL-2 signaling in responding T cells was mediated by upregulation of Suppressor Of Cytokine Signaling 3 (SOCS3). This mechanism could be mimicked by pharmacological Janus Kinase-1 (JAK1) inhibition. Collectively, our results identify an unrecognized mechanism that prevents the development of unwanted Th2 cell responses and associated diseases and outline potential preventive interventions.


Subject(s)
Interleukin-6 , Th2 Cells , Humans , Th2 Cells/metabolism , Interleukin-2 , Inflammation , Immunoglobulin E , Cytokines/metabolism , Suppressor of Cytokine Signaling 3 Protein
19.
AIDS Res Hum Retroviruses ; 39(7): 350-366, 2023 07.
Article in English | MEDLINE | ID: mdl-36762930

ABSTRACT

The most potent and broad HIV envelope (Env)-specific antibodies often when reverted to their inferred germline versions representing the naive B cell receptor, fail to bind Env, suggesting that the initial responding B cell population not only exclusively comprises a naive population, but also a pre-existing cross-reactive antigen-experienced B cell pool that expands following Env exposure. Previously we isolated gp120-reactive monoclonal antibodies (mAbs) from participants in HVTN 105, an HIV vaccine trial. Using deep sequencing, focused on immunoglobulin G (IgG), IgA, and IgM, VH-lineage tracking, we identified four of these mAb lineages in pre-immune peripheral blood. We also looked through the ∼7 month postvaccination bone marrow, and interestingly, several of these lineages that were found in prevaccination blood were still persistent in the postvaccination bone marrow, including the CD138+ long-lived plasma cell compartment. The majority of the pre-immune lineage members included IgM, however, IgG and IgA members were also prevalent and exhibited somatic hypermutation. These results suggest that vaccine-induced gp120-specific antibody lineages originate from both naive and cross-reactive memory B cells. ClinicalTrials.gov NCT02207920.


Subject(s)
AIDS Vaccines , HIV Infections , HIV-1 , Humans , HIV Infections/prevention & control , HIV Antibodies , Vaccination , HIV Envelope Protein gp120 , Immunoglobulin G , Antibodies, Monoclonal , Immunoglobulin A , Immunoglobulin M , Antibodies, Neutralizing
20.
Front Immunol ; 14: 1158493, 2023.
Article in English | MEDLINE | ID: mdl-37575256

ABSTRACT

Introduction: Data from patient cohorts and mouse models of atopic dermatitis, food allergy and asthma strongly support a role for chitinase-3-like-1 protein (CHI3L1) in allergic disease. Methods: To address whether Chi3l1 also contributes to TH2 responses following nematode infection, we infected Chi3l1 -/- mice with Heligmosomoides polygyrus (Hp) and analyzed T cell responses. Results: As anticipated, we observed impaired TH2 responses in Hp-infected Chi3l1 -/- mice. However, we also found that T cell intrinsic expression of Chi3l1 was required for ICOS upregulation following activation of naïve CD4 T cells and was necessary for the development of the IL-4+ TFH subset, which supports germinal center B cell reactions and IgE responses. We also observed roles for Chi3l1 in TFH, germinal center B cell, and IgE responses to alum-adjuvanted vaccination. While Chi3l1 was critical for IgE humoral responses it was not required for vaccine or infection-induced IgG1 responses. Discussion: These results suggest that Chi3l1 modulates IgE responses, which are known to be highly dependent on IL-4-producing TFH cells.


Subject(s)
Chitinases , Helminthiasis , Helminths , Animals , Mice , Chitinases/metabolism , Immunoglobulin E , Interleukin-4/metabolism , T-Lymphocytes, Helper-Inducer
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