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Journal of Translational Medicine

, 14:138

First Online: 17 May 2016Received: 30 December 2015Accepted: 07 May 2016DOI: 10.1186-s12967-016-0900-2

Cite this article as: de Lollo, C., de Moraes Vasconcelos, D., da Silva Oliveira, L.M. et al. J Transl Med 2016 14: 138. doi:10.1186-s12967-016-0900-2


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 CD45RACCR7 in the peripheral blood and increased expression of CD38 in terminally differentiated CD8 T cells CD45RACCR7. Furthermore, a decreased frequency of naïve regulatory T cells CD45RAFoxp3, but not of activated regulatory T cells CD45RAFoxp3 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 CD3CD4CXCR5PD-1ICOS 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 TNFin 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.

KeywordsCommon variable immunodeficiency Exhaustion and activation markers Toll-like receptor agonists Tc22-Th22 Polyfunctional T cells Electronic supplementary materialThe online version of this article doi:10.1186-s12967-016-0900-2 contains supplementary material, which is available to authorized users.

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Autor: Camila de Lollo - Dewton de Moraes Vasconcelos - Luanda Mara da Silva Oliveira - Tiago de Oliveira Titz - Magda Carneiro


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