Journal Article

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

Harling, Kirstin, Owusu-Dabo, Ellis, Olbrich, Laura, Nausch, Norman, Mayatepek, Ertan, Adankwah, Ernest, Afum-Adjei Awuah, Anthony, Lang, Franziska, Lundtoft, Christian, Jacobsen, Marc, Kohns, Malte, Rimpler, Jens

2017

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Aberration / Acquired immune deficiency syndrome / Adult / Aged / AIDS / Autoimmunity / Biology and Life Sciences / Blood plasma / Case-Control Studies / CD4 antigen / CD4-Positive T-Lymphocytes - immunology / Cell proliferation / Control / Development and progression / Exhaustion / Female / Health aspects / HIV / HIV patients / Human immunodeficiency virus / Human performance / Humans / Immunity / Immunodeficiency / In vitro methods and tests / Interleukin 7 / Interleukin-7 - blood / Interleukin-7 - genetics / Interleukin-7 - immunology / Lymphocytes / Lymphocytes T / Male / Markers / Medicine and Health Sciences / Memory / Middle Aged / Mycobacterium tuberculosis - genetics / Mycobacterium tuberculosis - physiology / Patients / PD-1 protein / Phosphorylation / Post-transcription / Receptors, Interleukin-7 - blood / Receptors, Interleukin-7 - genetics / Receptors, Interleukin-7 - immunology / Recovery / Research and Analysis Methods / Risk factors / Signaling / Stat5 protein / STAT5 Transcription Factor - genetics / STAT5 Transcription Factor - immunology / Suppressor of Cytokine Signaling 3 Protein - genetics / Suppressor of Cytokine Signaling 3 Protein - immunology / T cell receptors / T cells / Therapy / Transcription / Tuberculosis / Tuberculosis - immunology / Tuberculosis - microbiology / Young Adult