Increased (6 exon) interleukin-7 production after M. tuberculosis infection and soluble interleukin-7 receptor expression in lung tissue

Abstract

Interleukin-7 (IL-7) and the IL-7 receptor (IL-7R) have been shown to be alternatively spliced in infectious diseases. We tested IL-7 and IL-7R splicing in a tuberculosis (TB)-vaccine/Mycobacterium tuberculosis (Mtb)-challenge model in non-human primates (NHPs). Differential IL-7 splicing was detected in peripheral blood mononuclear cells (PBMCs) from 15/15 NHPs showing 6 different IL-7 spliced isoforms. This pattern did not change after infection with virulent Mtb. We demonstrated increased IL-7 (6 exon) and IL-17 protein production in lung tissue along with concomitant decreased transforming growth factor-b (TGF-b) from NHPs (vaccinated with a recombinant BCG (rBCG)) who showed increased survival after Mtb challenge. IL-7 increased IL-17 and interferon-g (IFN-g) gene and protein expression in PBMCs. Mtb-infected NHPs showed differential IL-7R splicing associated with the anatomical location and tissue origin, that is, in lung tissue, hilus, axillary lymph nodes (LNs) and spleen. Differential splicing of the IL-7R was typical for healthy (non-Mtb infected) and for Mtb-infected lung tissue with a dominant expression of soluble IL-7R (sIL-7R) receptor lacking exon 6 (9:1 ratio of sIL-7R/cell-bound IL-7R). Differential ratios of cell-bound vs sIL-7R could be observed in hilus and axillary LNs from Mtb-infected NHPs with an inversed ratio of 1:9 (sIL-7R/cell-bound IL-7R) in spleen and PBMCs. Soluble IL-7R is exclusively present in lung tissue.

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.…”

IL-7: The global builder of the innate lymphoid network and beyond, one niche at a time

“…The increased sIL-7R levels did not, however, correlate with either viral load or the size of CD4 + T cell population [30]. sIL-7R predominates in lung tissues, perhaps indicating a differential role for sIL-7R in a local microenvironment-specific manner [31]. These data collectively suggest that IL-7 has a diverse functional profile in different localized microenvironments, with roles in both the maintenance and regulation of tissue specific lymphocyte populations and in the development and function of tissues (see below), but the specific dynamics of IL-7 activities in localized microenvironments have not been precisely measured.…”

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

“…Increased IL-7 and soluble IL-7R expression in pulmonary tissue of primates with tuberculosis was found, indicating a possible role of IL-7 metabolism in tuberculosis pathogenesis [37, 38]. Furthermore IL-7 was shown to promote survival and to improve BCG vaccination efficacy in M .…”