A defect in the early phase of T-cell receptor-mediated T-cell activation in patients with common variable immunodeficiency

Abstract

Common variable immunodeficiency (CVID) is characterized by an impairment of specific antibody production and a decrease in all or selected Ig isotypes. Abnormalities at the level of the B cells, T cells, and antigen-presenting cells have been described. In the present study, we have focused our attention on T-cell activation in CVID. T cells from 15 of 24 patients failed to respond to recall antigens (eg, tetanus toxoid, Escherichia coli). Of these 15 patients, 11 were studied in detail and showed significantly decreased T-cell proliferative responses and/or decreased interleukin-2 and interferon- gamma production on T-cell receptor-mediated stimulation with recall antigens and superantigens (staphylococcal enterotoxins [SE]); however, T-cell response to mitogens (anti-CD3 monoclonal antibody, phytohemagglutinin) was normal. The defect in interleukin-2 and interferon-gamma release on tetanus toxoid stimulation could also be documented in purified CD4 T cells of the patients and was present in patients with high and normal CD8 counts alike. Furthermore, patients' T cells failed to mount a significant elevation in free intracellular calcium (Ca++ flux) in response to superantigen, whereas the response to phorbol myristate acetate and ionomycin, bypassing receptor-mediated signaling, was unimpaired. These results indicate a defect in the early phase of T-cell activation after triggering of the T-cell receptor in a significant subgroup of CVID patients.

Intracellular cytokine production by human CD4+ and CD8+ T cells from normal and immunodeficient donors using directly conjugated anti-cytokine antibodies and three-colour flow cytometry

“…There is much evidence for a reduction in IL-2 production in CVID. This comes from mitogenic studies measuring DNA synthesis, IL-2 mRNA and IL-2 secreted [4][5][6]13,14]. However, we now show with the directly conjugated anti-IL-2 antibody that there is no difference between CVID and normals in the mean proportion of CD4 + or CD8 + cells making IL-2.…”

“…Since we and others have reported that some CVID patients have subnormal DNA synthesis in response to PHA [4], we compared PHA with PMA and ionomycin for the kinetic induction of IL-2, IFNand TNF-in normal cells. PHA was far less effective than PMA and ionomycin and no significant cytokine 520 expression was seen in normal CD4 + cells for up to 14 h of stimulation.…”

“…Several reports suggest that there is a disturbance in CVID to the cytokine network between CD4 + T cells, CD8 + cells and monocytes. For example, IL-2 production is decreased in response to superantigens [4] or mitogens [5,6] and a clinical trial of IL-2 therapy has been attempted [7]. Furthermore, IFNexpression in response to antigen is reported to be reduced in CVID [2].…”

Defective integration of activating signals derived from the T cell receptor (TCR) and costimulatory molecules in both CD4+ and CD8+ T lymphocytes of common variable immunodeficiency (CVID) patients

“…Applying an experimental system free of APC, stimulation of the TCR in combination with distinct costimulatory molecules enabled us to analyse further the nature of the defect. Previous studies reported defective T cell responses to recall antigens in patients with CVID [8][9][10]34,35], and in a recent study impaired antigen response was attributed to a , CD40L expression in this cell population. A marker (Ml) was set to identify the percentage of CD40L' cells.…”

Common variable immunodeficiency (CVID): exploring the multiple dimensions of a heterogeneous disease

“…In this regard, 15 years ago, work demonstrated a decreased Ca ++ signal in T cells of some CVID patients. 58 And recently, a strong correlation between decreased BCR-induced Ca ++ signaling and CVID patients with low percentage of smB cells, but expansion of CD21 low B cells (Freiburg classification group Ia; Ref. 3), endorsed the classification and demonstrated a cell-intrinsic activation defect in B cells of these patients.…”