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

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.

Interleukin-7 receptor α-chain haplotypes differentially affect soluble IL-7 receptor and IL-7 serum concentrations in children with type 1 diabetes

“…This is supported by the absence of correlation between sIL‐7R and IL‐7 serum concentrations. Similarly, we did not find any correlation between IL‐7 and sIL‐7R serum concentration in a previous study of tuberculosis patients and controls, although both IL‐7 and sIL‐7R serum concentration showed pathognomonic changes and normalization during recovery . This suggested disease‐specific but largely independent regulation of serum IL‐7 and sIL‐7R levels .…”

“…Similarly, we did not find any correlation between IL‐7 and sIL‐7R serum concentration in a previous study of tuberculosis patients and controls, although both IL‐7 and sIL‐7R serum concentration showed pathognomonic changes and normalization during recovery . This suggested disease‐specific but largely independent regulation of serum IL‐7 and sIL‐7R levels . As an alternative explanation, one could hypothesize that the protective haplotype affects mIL‐7R functions.…”

“…Serum samples from both cohorts were concomitantly thawed and quantification of sIL‐7R was performed as previously described . In brief, anti‐human CD127 (IL‐7Rα)‐labeled beads (1 μL) were incubated with serum samples (50 μL) for 1 hour at room temperature.…”

Th1 cytokines, true functional signatures for protective immunity against TB?

“…Maeurer et al 67 Singh et al 68 Lundtoft et al 69 Rane et al 70 Lazarevic et al 71 Saito et al 72 Umemura et al 73 Chandrashekara et al 74 Pydi et al 75 IL-10 PCR, EIA, ELISA Mice deficient in T-cell-derived (but not monocyte-derived) IL-10 showed significantly reduced lung bacterial loads during chronic Mtb infection compared to IL-10-competent mice. Transgenic mice overexpressing IL-10 exhibited increasing bacterial numbers in the lungs and showed evidence of TB reactivation during chronic infection compared to WT controls.…”

Group 2 ILCs: A way of enhancing immune protection against human helminths?

“…Regulation of IL‐7 signalling is much more complex and could depend on the availability of IL‐7 and levels of soluble IL‐7Rα (generated by alternative splicing), which has been shown to inhibit IL‐7 uptake or function as IL‐7 reservoir . Aberrant levels of plasma IL‐7 and soluble IL‐7R were recently shown in the context of human tuberculosis . In addition, modulation of downstream signalling in particular of the JAK‐STAT pathway including modulation of SOCS may influence homoeostasis and responsiveness of human ILC2s.…”