TLT2 Suppresses Th1 Response by Promoting IL-6 Production in Monocyte Through JAK/STAT3 Signal Pathway in Tuberculosis

Abstract

The function of triggering receptor expressed on myeloid cell-like transcript 2 (TLT2) has not been characterized and their role in pulmonary tuberculosis (TB) remains unclear. In this study, we found that surface TLT2 was up-regulated in human monocytes of patients with active TB compared to healthy subjects. In vitro, TLT2 expression was induced in human monocyte cell line THP-1 cells after bacillus Calmette-Guérin (BCG) or Mycobacterium tuberculosis (Mtb) H37Rv infection. Knockdown of TLT2 by siRNA transfection suppressed IL-6 expression, whereas over-expression of TLT2 increased IL-6 production in THP-1 cells infected by H37Rv. TLT2 + CD14 + monocytes produced higher level of IL-6 compared to TLT2 − subset in active TB patients. Western blot and immunocoprecipitation revealed that TLT2 interacted with kinase JAK1/JAK2/Tyk2 to enhance STAT3 phosphorylation. Moreover, we showed that tyrosine residues 297 and 315 of TLT2 cytoplasmic domain were involved in STAT3 activation. In monocyte/CD4 + T cell co-culture assay, blockage of TLT2 fusion protein facilitated IFN-γ production by CD4 + T cells. Plate count assay showed that monocyte-mediated bacterial killing was promoted by TLT2 fusion protein. In vivo treatment with TLT-2 fusion protein reduced IL-6 production by macrophage but increased IFN-γ production by CD4 + T cell in H37Rv and BCG infected mice. Furthermore, TLT2 fusion protein attenuated inflammation, and reduced bacterial load in lung of infected mice. Together, these findings demonstrate that TLT2 negatively regulates Th1 response against mycobacterial infection, which promotes IL-6 production through JAK/STAT3 signal pathway.

TARM-1 Is Critical for Macrophage Activation and Th1 Response in Mycobacterium tuberculosis Infection

“…injection of H37Rv show organized granulomas containing T cells and macrophages that resembled lesions observed in human TB (31). In our study, H&E staining showed pathologic changes characterized by lung destruction, granuloma formation, and immune cell infiltrates, as reported by previous studies and by others and us (32,33). Although TARM-1 enhanced the activation of macrophage and Th1 differentiation in vivo, TARM-1 blockade aggravated lung pathology in mice after H37Rv infection and increased bacterial load.…”

STAT3 and SPI1, may lead to the immune system dysregulation and heterotopic ossification in ankylosing spondylitis

“…STAT3 plays a key role in activating NKT cells by targeting its downstream MHC class I-related chain (MIC) [ 22 ]. The activation of STAT3 may suppresses Th1 response during tuberculosis infection [ 23 ]. TIRC7 inhibits Th1 cells by upregulating the expression of CTLA‑4 and STAT3 in mice with acute graft‑versus‑host disease [ 24 ].…”

Immune checkpoint of B7-H3 in cancer: from immunology to clinical immunotherapy

“…Using proteomics analysis and TLT-2 knockdown, Xu and colleagues revealed that TLT-2 activates NF-κB signaling by inhibiting IκBα to promote the expression of granzyme B (GZMB) and enhance the immune function and proliferation ability of CD8 + T cells [ 29 ]. However, in contrast to its overall proinflammatory effect on other cell types, TLT-2 expressed in monocytes promotes interleukin-6 (IL-6) expression via the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway, blocks Th1 differentiation and hinders the immune response to tuberculosis [ 30 ]. These studies suggest that TLT-2 is an important modulator of both the innate and adaptive immune systems.…”