Common variable immunodeficiency–associated endotoxemia promotes early commitment to the T follicular lineage
| Autor: | Taylor Olmsted Kim, Neil Romberg, E. John Wherry, Patricia Takach, Jennifer Heimall, Takuya Ohtani, Kathleen E. Sullivan, Scott Feldman, Olajumoke Fadugba, Caroline Khanna, Melissa Trofa, Michele P. Lambert, Soma Jyonouchi, Jenny M. Despotovic, Melanie A. Ruffner, Sarah E. Henrickson, Bertram Bengsch, Brian E. Nolan, Carole Le Coz |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 0301 basic medicine Adolescent Regulatory T cell medicine.medical_treatment Immunology Population T-Lymphocytes Regulatory Article Hypogammaglobulinemia 03 medical and health sciences 0302 clinical medicine medicine Humans Immunology and Allergy Child education B-Lymphocytes education.field_of_study business.industry Common variable immunodeficiency IgA Deficiency FOXP3 Cell Differentiation Middle Aged medicine.disease Endotoxemia Common Variable Immunodeficiency 030104 developmental biology medicine.anatomical_structure Cytokine Immunoglobulin class switching Child Preschool Female Cytokine receptor business 030215 immunology |
| Zdroj: | J Allergy Clin Immunol |
| ISSN: | 0091-6749 |
| DOI: | 10.1016/j.jaci.2019.08.007 |
| Popis: | Background Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numeric and/or functional TH cell alterations. The causes, interrelationships, and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia, autoantibody production, or both remain unclear. Objective We sought to determine how circulating CD4+ T cells are altered in CVID subjects with autoimmune cytopenias (AICs; CVID+AIC) and the causes of these derangements. Methods Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4+ T cells. Differences between subject groups were confirmed in a large and genetically diverse cohort of CVID subjects (n = 69) by using flow cytometry, transcriptional profiling, multiplex cytokine/chemokine detection, and a suite of in vitro functional assays measuring naive T-cell differentiation, B-cell/T-cell cocultures, and regulatory T-cell suppression. Results Although CD4+ TH cell profiles from healthy donors and CVID subjects without AICs were virtually indistinguishable, T cells from CVID+AIC subjects exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency–associated endotoxemia and endotoxin-induced expression of activin A and inducible T-cell costimulator ligand. The resulting enlarged circulating follicular helper T-cell population from CVID+AIC subjects provided efficient help to receptive healthy donor B cells but not unresponsive CVID B cells. Despite this, circulating follicular helper T cells from CVID+AIC subjects exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with regulatory T-cell suppression assays and were associated with autoantibody production. Conclusions Endotoxemia is associated with early commitment to the follicular T-cell lineage in IgA-deficient CVID subjects, particularly those with AICs. |
| Databáze: | OpenAIRE |
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