Abstract
BackgroundInfections caused by bacteria or viruses are frequent in common variable immunodeficiency (CVID) patients due to antibody deficiencies, which may be associated with altered T cell function. CVID patients are frequently in contact with pathogen-associated molecular patterns (PAMPs), leading to the activation of innate immunity through Toll-like receptors (TLR) affecting T cell activation. We evaluated the effect of TLR activation on T cells in CVID patients undergoing intravenous immunoglobulin (IVIg) replacement using synthetic ligands.MethodsExpression of exhaustion, activation and maturation markers on T cells from peripheral blood as well as regulatory T cells and follicular T cells in peripheral blood mononuclear cells (PBMCs) from CVID and healthy individuals were evaluated by flow cytometry. PBMCs cultured with TLR agonists were assessed for intracellular IFN-γ, TNF, IL-10, IL-17a or IL-22 secretion as monofunctional or polyfunctional T cells (simultaneous cytokine secretion) by flow cytometry.ResultsWe found increased expression of the exhaustion marker PD-1 on effector memory CD4+ T cells (CD45RA−CCR7−) in the peripheral blood and increased expression of CD38 in terminally differentiated CD8+ T cells (CD45RA+CCR7−). Furthermore, a decreased frequency of naïve regulatory T cells (CD45RA+Foxp3low), but not of activated regulatory T cells (CD45RA−Foxp3high) was detected in CVID patients with splenomegaly, the non-infectious manifestation in this CVID cohort (43.7 %). Moreover, the frequency of peripheral blood follicular helper T cells (CD3+CD4+CXCR5+PD-1+ICOS+) was similar between the CVID and control groups. Upon in vitro TLR3 activation, a decreased frequency of CD8+ T cells secreting IFN-γ, IL-17a or IL-22 was detected in the CVID group compared to the control group. However, a TLR7/TLR8 agonist and staphylococcal enterotoxin B induced an increased Th22/Tc22 (IL-22+, IFN-γ−, IL-17a−) response in CVID patients. Both TLR2 and TLR7/8/CL097 activation induced an increased response of CD4+ T cells secreting three cytokines (IL-17a, IL-22 and TNF)in CVID patients, whereas CD8+ T cells were unresponsive to these stimuli.ConclusionThe data show that despite the unresponsive profile of CD8+ T cells to TLR activation, CD4+ T cells and Tc22/Th22 cells are responsive, suggesting that activation of innate immunity by TLRs could be a strategy to stimulate CD4+ T cells in CVID.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0900-2) contains supplementary material, which is available to authorized users.
Highlights
Infections caused by bacteria or viruses are frequent in common variable immunodeficiency (CVID) patients due to antibody deficiencies, which may be associated with altered T cell function
Exhaustion/activation T cell markers and frequency of effector/regulatory T cells in CVID To evaluate whether the activation of innate immunity via Toll-like receptors (TLR) activation could enhance the adaptive response, we previously evaluated the activation/ exhaustion profiles of CD4+ and CD8+ T cells
Considering that intravenous immunoglobulin (IVIg) treatment partially restores CD4+ T cell activation [17], we evaluated the markers related to exhaustion, resting/naïve status (interleukin (IL)-7 receptor alpha chain (CD127), and activation (CD38) at different stages of T cell maturation as well as in regulatory T cells in the CVID and HC groups
Summary
Infections caused by bacteria or viruses are frequent in common variable immunodeficiency (CVID) patients due to antibody deficiencies, which may be associated with altered T cell function. CVID patients are fre‐ quently in contact with pathogen-associated molecular patterns (PAMPs), leading to the activation of innate immu‐ nity through Toll-like receptors (TLR) affecting T cell activation. Upon pathogenassociated molecular pattern (PAMP) expression, pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), trigger intracellular signals to innate immune cells to contain the infection and return to homeostasis [5]. Defective TLR7 and TLR9 signaling in B cells and plasmacytoid dendritic cells (pDCs), deficient IFN-α secretion, and impaired B cell function alter innate immune responses in CVID, preventing TLR-mediated enhancement of humoral immunity in vivo and possibly increasing susceptibility to enteroviral and rhinoviral infections [6, 7]
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