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

Carole Le Coz, Bertram Bengsch, Caroline Khanna, Melissa Trofa, Takuya Ohtani, Brian E. Nolan, Sarah E. Henrickson, Michele P. Lambert, Taylor Olmsted Kim, Jenny M. Despotovic, Scott Feldman, Olajumoke O. Fadugba, Patricia Takach, Melanie Ruffner, Soma Jyonouchi, Jennifer Heimall, Kathleen E. Sullivan, E. John Wherry, Neil Romberg*

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1660-1673
Number of pages14
JournalJournal of Allergy and Clinical Immunology
Volume144
Issue number6
DOIs
StatePublished - Dec 2019
Externally publishedYes

Keywords

  • Common variable immunodeficiency
  • activin A
  • autoimmune cytopenias
  • endotoxin
  • follicular helper T cell
  • recent thymic emigrant
  • regulatory T cell
  • time-of-flight cytometry

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Le Coz, C., Bengsch, B., Khanna, C., Trofa, M., Ohtani, T., Nolan, B. E., Henrickson, S. E., Lambert, M. P., Kim, T. O., Despotovic, J. M., Feldman, S., Fadugba, O. O., Takach, P., Ruffner, M., Jyonouchi, S., Heimall, J., Sullivan, K. E., Wherry, E. J., & Romberg, N. (2019). Common variable immunodeficiency–associated endotoxemia promotes early commitment to the T follicular lineage. Journal of Allergy and Clinical Immunology, 144(6), 1660-1673. https://doi.org/10.1016/j.jaci.2019.08.007