TCR ζ Down-Regulation under Chronic Inflammation Is Mediated by Myeloid Suppressor Cells Differentially Distributed between Various Lymphatic Organs

Abstract

T cell AgR ζ chain down-regulation associated with T cell dysfunction has been described in cancer, infectious, and autoimmune diseases. We have previously shown that chronic inflammation is mandatory for the induction of an immunosuppressive environment leading to this phenomenon. To identify the key immunosuppressive components, we used an in vivo mouse model exhibiting chronic inflammation-induced immunosuppression. Herein, we demonstrate that: 1) under chronic inflammation secondary lymphatic organs display various immunological milieus; ζ chain down-regulation and T cell dysfunction are induced in the spleen, peripheral blood, and bone marrow, but not in lymph nodes, correlating with elevated levels of Gr1+Mac-1+ myeloid suppressor cells (MSC); 2) MSC are responsible for the induction of such an immunosuppression under both normal and inflammatory conditions; and 3) normal T cells administered into mice exhibiting an immunosuppressive environment down-regulate their ζ expression. Such an environment is anticipated to limit the success of immunotherapeutic strategies based on vaccination and T cell transfer, which are currently under investigation for immunotherapy of cancer.

TNFR1 signalling is a critical checkpoint for developing macrophages that control of T‐cell proliferation

“…Compared with unstimulated T cells, activation with WT Mu led to lower levels of CD3f (Fig. 2b) consistent with T-cell inhibition, 25 whereas activation with TNFR1 )/) Mu led to CD3f up-regulation, consistent with normal activation 26 ( Fig. 2b).…”

Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model

“…A down-regulation of ζ-chain expression has been previously described not only in cancer (43,44), but also in chronic inflammation associated with sustained antigenic stimulation (19,21), suggesting again a striking resemblance of these two pathological conditions. We observed a direct effect of MDSCs on TCR ζ-chain expression in coculture experiments.…”

“…MDSC immunosuppressive activity in tumor-bearing hosts inhibiting antitumor T-cell responses was reported to be a result of the activation of inducible NOS and arginase (ARG)-1, leading to L-arginine depletion and increased production of NO and reactive oxygen species (11,(16)(17)(18). One of the major features of MDSC-induced impairment of T-cell functions is associated with a pronounced down-regulation of the Tcell receptor (TCR) ζ-chain expression (19,20), which plays a key role in coupling the TCR-mediated antigen recognition to diverse signal transduction pathways (21).…”

Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy

“…30,31 Through a variety of mechanisms that inhibit T cell activation and expansion, including the production of arginase and inducible nitric oxide synthase (iNOS), reactive oxygen species and/or reactive nitrogen species (ROS and/or RNS), release of IL-10, expansion of regulatory T cells (Tregs), and inhibition of T cell migration, MDSCs have been shown to promote immunosuppression and tumor progression. [32][33][34][35][36] Targeting specific mechanisms of immune suppression are critical to increasing the effectiveness of immunotherapies. Herein, we aimed to test the hypothesis that MDSCs accumulate in the GBM TME and inhibit tumor-specific immunity.…”