Common variable immunodeficiency–associated endotoxemia promotes early commitment to the T follicular lineage

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...

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Published in:	Journal of allergy and clinical immunology Vol. 144; no. 6; pp. 1660 - 1673
Main Authors:	Le Coz, Carole, Bengsch, Bertram, Khanna, Caroline, Trofa, Melissa, Ohtani, Takuya, Nolan, Brian E., Henrickson, Sarah E., Lambert, Michele P., Kim, Taylor Olmsted, Despotovic, Jenny M., Feldman, Scott, Fadugba, Olajumoke O., Takach, Patricia, Ruffner, Melanie, Jyonouchi, Soma, Heimall, Jennifer, Sullivan, Kathleen E., Wherry, E. John, Romberg, Neil
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01.12.2019 Elsevier Limited
Subjects:	Activin activin A Age Anemia Autoantibodies autoimmune cytopenias CD4 antigen Cell differentiation Cell lineage Chemokines Common variable immunodeficiency Costimulator Cytokines Cytopenia Endotoxemia endotoxin Enrollments Flow cytometry follicular helper T cell Hypogammaglobulinemia Immunoglobulin A Lymphocytes B Lymphocytes T Pathogenesis recent thymic emigrant regulatory T cell Signal transduction Software Thymus time-of-flight cytometry Transcription RTE Common variable immunodeficiency CVID−AIC ITP t-SNE FACS follicular helper T cell CVID time-of-flight cytometry TFH AIC TLR ICOS CSR Treg recent thymic emigrant autoimmune cytopenias CFSE ICOSL regulatory T cell FOXP3 ES CVID+AIC activin A HD cTFH CyTOF PD-1 endotoxin AIHA
ISSN:	0091-6749, 1097-6825, 1097-6825
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Summary:	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. 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. 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. 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. Endotoxemia is associated with early commitment to the follicular T-cell lineage in IgA-deficient CVID subjects, particularly those with AICs. [Display omitted]
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Feature-1 content type line 23 Author contributions: CLC, BB, CK, TO, MT, BEN and SEH performed experiments and analyzed data. MPL, SF, OOF, MR, SJ, JH, PT, KES, JMD, TOK and NR provided human samples. EJW and NR were responsible for study design. CLC and NR wrote the manuscript. All authors reviewed the manuscript and provided scientific input.
ISSN:	0091-6749 1097-6825 1097-6825
DOI:	10.1016/j.jaci.2019.08.007