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 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.
Highlights
T cells are crucial for protection against Mycobacterium (M.) tuberculosis infection but biomarkers that characterise T-cell failure and progression towards tuberculosis disease are not available [1]
In order to evaluate the potential impact of IL-7 on tuberculosis, we characterised various parameters involved in the IL-7response of tuberculosis patients and healthy contacts
Despite IL-7 being available at higher plasma levels among tuberculosis patients, the T-cell response to IL-7 was impaired when compared to healthy contacts
Summary
T cells are crucial for protection against Mycobacterium (M.) tuberculosis infection but biomarkers that characterise T-cell failure and progression towards tuberculosis disease are not available [1]. CD4+ T cells are key to anti-mycobacterial immune protection [2] and CD4+ Tcell deficiency, e.g. of AIDS patients, results in increased susceptibility against tuberculosis [3,4,5]. T-cell exhaustion impairs immunity against chronic viral infections and harms memory T-cell potential [9]. IL-7 induced T-cell memory was hampered in the presence of persistent antigen and inflammation as seen for chronic viral infections [11]. In AIDS patients, failure of immune reconstitution is accompanied by a dysfunctional T-cell response that showed features of senescence and exhaustion [12,13,14]. Persistent inflammation characterised e.g. by increased IL-6 serum concentrations from AIDS patients were found to correlate with T-cell exhaustion/senescence and impaired T-cell response to IL-7 [14, 15]. Impaired Tcell response to IL-7 was detected in immune failure patients [13,14,15, 18,19,20]
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