Dataset Information

Impaired T-cell receptor activation in IL-1 receptor-associated kinase-4-deficient patients.

ABSTRACT:

Background

IL-1 receptor-associated kinase 4 (IRAK-4) is an effector of the Toll-like receptor and IL-1 receptor pathways that plays a critical role in innate immune responses. The role of IRAK-4 in adaptive immune functions in human subjects is incompletely understood.

Objective

We sought to evaluate T-cell function in IRAK-4 deficient patients.

Methods

We compared upregulation of CD25 and CD69 on T cells and production of IL-2, IL-6, and IFN-gamma after stimulation of PBMCs from 4 IRAK-4-deficient patients and healthy control subjects with anti-CD3 and anti-CD28.

Results

Upregulation of CD25 and CD69 on T cells and production of IL-6 and IFN-gamma, but not IL-2, was significantly reduced in IRAK-4-deficient patients.

Conclusions

IRAK-4-deficient patients have defects in T-cell activation.

SUBMITTER: McDonald DR

PROVIDER: S-EPMC2917474 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Publications

Impaired T-cell receptor activation in IL-1 receptor-associated kinase-4-deficient patients.

McDonald Douglas R DR Goldman Frederick F Gomez-Duarte Oscar D OD Issekutz Andrew C AC Kumararatne Dinakantha S DS Doffinger Rainer R Geha Raif S RS

The Journal of allergy and clinical immunology 20100801 2

<h4>Background</h4>IL-1 receptor-associated kinase 4 (IRAK-4) is an effector of the Toll-like receptor and IL-1 receptor pathways that plays a critical role in innate immune responses. The role of IRAK-4 in adaptive immune functions in human subjects is incompletely understood.<h4>Objective</h4>We sought to evaluate T-cell function in IRAK-4 deficient patients.<h4>Methods</h4>We compared upregulation of CD25 and CD69 on T cells and production of IL-2, IL-6, and IFN-gamma after stimulation of PBM ...[more]

PMID: 20621347

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Project description:T-cell proliferation and generation of protective memory during chronic infections depend on Interleukin-7 (IL-7) availability and receptivity. Regulation of IL-7 receptor (IL-7R) expression and signalling are key for IL-7-modulated T-cell functions. Aberrant expression of soluble (s) and membrane-associated (m) IL-7R molecules is associated with development of autoimmunity and immune failure in acquired immune deficiency syndrome (AIDS) patients. Here we investigated the role of IL-7/IL-7R on T-cell immunity in human tuberculosis. We performed two independent case-control studies comparing tuberculosis patients and healthy contacts. This was combined with follow-up examinations for a subgroup of tuberculosis patients under therapy and recovery. Blood plasma and T cells were characterised for IL-7/sIL-7R and mIL-7R expression, respectively. IL-7-dependent T-cell functions were determined by analysing STAT5 phosphorylation, antigen-specific cytokine release and by analysing markers of T-cell exhaustion and inflammation. Tuberculosis patients had lower soluble IL-7R (p < 0.001) and higher IL-7 (p < 0.001) plasma concentrations as compared to healthy contacts. Both markers were largely independent and aberrant expression normalised during therapy and recovery. Furthermore, tuberculosis patients had lower levels of mIL-7R in T cells caused by post-transcriptional mechanisms. Functional in vitro tests indicated diminished IL-7-induced STAT5 phosphorylation and impaired IL-7-promoted cytokine release of Mycobacterium tuberculosis-specific CD4+ T cells from tuberculosis patients. Finally, we determined T-cell exhaustion markers PD-1 and SOCS3 and detected increased SOCS3 expression during therapy. Only moderate correlation of PD-1 and SOCS3 with IL-7 expression was observed. We conclude that diminished soluble IL-7R and increased IL-7 plasma concentrations, as well as decreased membrane-associated IL-7R expression in T cells, reflect impaired T-cell sensitivity to IL-7 in tuberculosis patients. These findings show similarities to pathognomonic features of impaired T-cell functions and immune failure described in AIDS patients.

Dataset Information

Impaired T-cell receptor activation in IL-1 receptor-associated kinase-4-deficient patients.

Background

Objective

Methods

Results

Conclusions

Publications

Impaired T-cell receptor activation in IL-1 receptor-associated kinase-4-deficient patients.

Similar Datasets

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