Aberrant plasma IL-7 and soluble IL-7 receptor levels indicate impaired T-cell response to IL-7 in human tuberculosis
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Date
2017
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PLOS
Abstract
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 autoim munity 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 per formed 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 deter mined by analysing STAT5 phosphorylation, antigen-specific cytokine release
and by ana lysing 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 normal ised during therapy and
recovery.
Furthermore, tuberculosis patients had lower levels ofmIL-7R in T cells caused by post-transcriptional mechanisms.
Functional in vitro tests indi cated diminished IL-7-induced STAT5 phosphorylation and impaired IL-7-promoted
cyto kine 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.
Description
This article is published by Plos and is also available at https://doi.org/10.1371/journal.ppat.1006425
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Citation
Lundtoft C, Afum-Adjei Awuah A, Rimpler J,Harling K, Nausch N, Kohns M, et al. (2017) Aberrant plasma IL-7 and soluble IL-7 receptor levels indicate impaired T-cell response to IL-7 in human tuberculosis