Aberrant plasma IL-7 and soluble IL-7 receptor levels indicate impaired T-cell response to IL-7 in human tuberculosis

PLoS Pathogens

Ernest Adankwah¹  Norman Nausch¹  Laura Olbrich¹  Ertan Mayatepek¹  Malte Kohns¹  Kirstin Harling¹  Christian Lundtoft¹  Ellis Owusu-Dabo¹  Franziska Lang¹  Anthony Afum-Adjei Awuah²  Marc Jacobsen²  Jens Rimpler³ 

[1] Department of General Pediatrics, Neonatology, and Pediatric Cardiology, University Children’s Hospital, Medical Faculty, Duesseldorf, Germany;Kumasi Centre for collaborative Research in Tropical Medicine (KCCR), Kumasi, Ghana;School of Medical Sciences, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana

关键词: Tuberculosis;    T cells;    Blood plasma;    Mycobacterium tuberculosis;    Phosphorylation;    Cloning;    Cytotoxic T cells;    Cytokines;   

DOI  :  10.1371/journal.ppat.1006425

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY