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

Abstract

Background: Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numeric and/or functional T H cell alterations. The causes, interrelationships, and consequences of CVID-associated CD4 1 T-cell derangements to hypogammaglobulinemia, autoantibody production, or both remain unclear. Objective: We sought to determine how circulating CD4 1 T cells are altered in CVID subjects with autoimmune cytopenias (AICs; CVID1AIC) and the causes of these derangements. Methods: Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4 1 T cells. Differences between subject groups were confirmed in a large and genetically diverse cohort of CVID subjects (n 5 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 1 T H cell profiles from healthy donors and CVID subjects without AICs were virtually indistinguishable, T cells from CVID1AIC subjects exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiencyassociated endotoxemia and endotoxin-induced expression of activin A and inducible T-cell costimulator ligand. The resulting enlarged circulating follicular helper T-cell population from CVID1AIC subjects provided efficient help to receptive healthy donor B cells but not unresponsive CVID B cells. Despite this, circulating follicular helper T cells from CVID1AIC 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.

Functions of Tfh Cells in Common Variable Immunodeficiency

“…As explained earlier, TFH can be divided into two subsets: the non-efficient helper TFH1 and the efficient helpers TFH2 and TFH17. Interestingly, we (75) and others (77,78,80) highlight a specific increase of the circulating TFH1 only in non-infectious CVID patients. Moreover, CXCR3 + (75) or Tbet + (78) cells were amplified in secondary lymphoid organs of CVID patients, suggesting that the blood observations reflect the GC counterpart.…”

“…A recent study from Le Coz et al highlighted that part of the naïve CD4 T cells from CVID patients with autoimmune cytopenias (AIC) are skewed toward a follicular commitment based on their expression of specific markers (CXCR5, PD-1, CCR7, CD38, ICOS, Tcell factor 1). In addition, some recently identified thymic emigrant cells (defined as CD45RA + CD31 + ) express CXCR5 and PD-1 in CVID patients with AIC (80). These data suggest that CD4 T cells present follicular aspects as early as thymic egress stage.…”

“…Moreover, TFH can differentiate from naive CD4 + T cells by interacting with different dendritic cell subsets or under the influence of several cytokines such as IL-12 (55), TGFβ (56) or Activin A (57). Notably, Martinez-Pomar et al reported high amounts of IL-12 in the sera of CVID patients (84), which was not confirmed by Le Coz et al (80). By contrast, they found an increase in plasma levels of Activin A, correlating with circulating TFH frequencies.…”

“…In contrast, Th17-oriented TFH were decreased. An increase in CD25 + CD127 − CXCR5 + PD-1 + cells was observed, but these cells do not present regulatory functions and still need to be further characterized (80). TFH1 are not efficient B helper cells, partly due to their poor production of IL-21 (38).…”

Gut Microbiota-Dependent Trimethylamine N-Oxide Associates With Inflammation in Common Variable Immunodeficiency

“…Furthermore, LPS and low serum IgA concentrations have been found to correlate with development of autoimmune cytopenias in CVID patients (31,32). We found no significant difference in LPS levels between CVID patients with serum IgA <0.1 g/L compared to CVID patients with IgA ≥ 0.1 g/L, or CVID patients with or without autoimmune cytopenia, organ specific autoimmunity or enteropathy (Supplementary Table 6).…”