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

• Published in: PLoS pathogens Vol. 13; no. 6; p. e1006425
• Main Authors: Lundtoft, Christian, Afum-Adjei Awuah, Anthony, Rimpler, Jens, Harling, Kirstin, Nausch, Norman, Kohns, Malte, Adankwah, Ernest, Lang, Franziska, Olbrich, Laura, Mayatepek, Ertan, Owusu-Dabo, Ellis, Jacobsen, Marc
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 05.06.2017; Public Library of Science (PLoS)
• Subjects: 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; Ghana
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1006425

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.