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

J Allergy Clin Immunol 2019 12 22;144(6):1660-1673. Epub 2019 Aug 22.

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:

Background: Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numeric and/or functional T 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 T 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.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2019.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900457PMC
December 2019

Publication Analysis

Top Keywords

cvid subjects
20
cvid+aic subjects
12
circulating follicular
8
subjects
8
subjects exhibited
8
follicular helper
8
circulating cd4
8
common variable
8
regulatory t-cell
8
subjects aics
8
commitment follicular
8
cells cvid+aic
8
early commitment
8
t-cell
7
follicular
6
cvid
6
cells
5
healthy donors
4
profiles healthy
4
cell profiles
4

Similar Publications