Carole Le Coz1, Bertram Bengsch2, Caroline Khanna1, Melissa Trofa1, Takuya Ohtani3, Brian E Nolan4, Sarah E Henrickson5, Michele P Lambert6, Taylor Olmsted Kim7, Jenny M Despotovic7, Scott Feldman8, Olajumoke O Fadugba8, Patricia Takach8, Melanie Ruffner1, Soma Jyonouchi9, Jennifer Heimall9, Kathleen E Sullivan5, E John Wherry10, Neil Romberg11. 1. Division of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, Pa. 2. Department of Medicine II, University Medical Center Freiburg, Freiburg, Germany. 3. Institute for Immunology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa. 4. Division of Rheumatology, Children's Hospital of Philadelphia, Philadelphia, Pa. 5. Division of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, Pa; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa; Institute for Immunology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa. 6. Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pa; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa. 7. Department of Pediatrics, Hematology/Oncology Section, Baylor College of Medicine, Houston, Tex. 8. Department of Medicine, Division of Allergy and Immunology,Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa. 9. Division of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, Pa; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa. 10. Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa; Institute for Immunology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa. 11. Division of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, Pa; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa; Institute for Immunology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa. Electronic address: rombergn@email.chop.edu.
Abstract
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.
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.
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