Highlights • Sepsis is the leading cause of death in critically ill patients and novel therapies are necessary. • Immune suppression is frequently associated with sepsis-related deaths. • Therapies ...or immunomodulatory agents that enhance the immune response should be considered. • Cytokines and co-inhibitory receptors represent potential immunomodulatory agents.
With the broad application of cancer immunotherapies such as immune checkpoint inhibitors in multiple cancer types, the immunological landscape in the tumor microenvironment (TME) has become ...enormously important for determining the optimal cancer treatment. Tumors can be immunologically divided into two categories: inflamed and non-inflamed based on the extent of immune cell infiltration and their activation status. In general, immunotherapies are preferable for the inflamed tumors than for non-inflamed tumors. Regulatory T cells (Tregs), an immunosuppressive subset of CD4+ T cells, play an essential role in maintaining self-tolerance and immunological homeostasis. In tumor immunity, Tregs compromise immune surveillance against cancer in healthy individuals and impair the antitumor immune response in tumor-bearing hosts. Tregs, therefore, accelerate immune evasion by tumor cells, leading to tumor development and progression in various types of cancer. Therefore, Tregs are considered to be a crucial therapeutic target for cancer immunotherapy. Abundant Tregs are observed in the TME in many types of cancer, both in inflamed and non-inflamed tumors. Diverse mechanisms of Treg accumulation, activation, and survival in the TME have been uncovered for different tumor types, indicating the importance of understanding the mechanism of Treg infiltration in each patient when selecting the optimal Treg-targeted therapy. Here, we review recent advances in the understanding of mechanisms leading to Treg abundance in the TME to optimize Treg-targeted therapy. Furthermore, in addition to the conventional strategies targeting cell surface molecules predominantly expressed by Tregs, reagents targeting molecules and signaling pathways specifically employed by Tregs for infiltration, activation, and survival in each tumor type are illustrated as novel Treg-targeted therapies. The effectiveness of immune precision therapy depends on conditions in the TME of each cancer patient.
Highlights • In the clinic, targeting blocking the CTLA-4 and PD-1 pathway is advantageous in cancer patients. • Preclinical studies show that B7-H4 and B7-H6 are promising targets in cancer. • ...VISTA, a novel B7 inhibitory ligand, maybe a therapeutic target in cancer and autoimmunity.
Multiple sclerosis (MS) is the most common demyelinating disease which mainly impacts the integrity of central nervous system (CNS). MS etiology is not clearly known but genetic, environmental ...factors and immune system are the most frequently explored risk factors. Adaptive immune responses have a critical role in MS pathogenesis in which auto-reactive T-cells and autoantibodies are main orchestrators. Immune responses are modulated by inhibitory molecules which regulates adaptive system activation and hemostasis interface. These molecules suppress immune responses through inhibition of cytokine secretion and T cell proliferation and subsequently reducing the inflammation and respective damage. Therefore the critical role of inhibitory molecules in regulating the healthy and safe immune responses make them very attractive target for immunotherapy. In this review paper, the role of inhibitory molecules expressed on the various immune cell types in MS pathogenesis and experimental autoimmune encephalomyelitis (EAE) animal model will be summarized.
•VISTA is one of the goals in the therapeutic target for MS treatment.•CTLA-4 polymorphisms do not correlate with MS susceptibility.•Modulating Lag-3 can affect the autoimmune disease as well as MS.•TIM3–galectin-9 pathway associated with auto-reactive T cells.•Modulation of PD1 and PD-L1 pathways holds promise in MS therapeutic potential.
Activated cytotoxic CD8
+
T cells can selectively kill target cells in an antigen-specific manner. However, their prolonged activation often has detrimental effects on tissue homeostasis and ...function. Indeed, overwhelming cytotoxic activity of CD8
+
T cells can drive immunopathology, and therefore, the extent and duration of CD8
+
T cell effector function needs to be tightly regulated. One way to regulate CD8
+
T cell function is their suppression through engagement of co-inhibitory molecules to their cognate ligands (e.g., LAG-3, PD-1, TIM-3, TIGIT and CTLA-4). During chronic antigen exposure, the expression of co-inhibitory molecules is associated with a loss of T cell function, termed T cell exhaustion and blockade of co-inhibitory pathways often restores T cell function. We addressed the effect of co-inhibitory molecule expression on CD8
+
T cell function during acute antigen exposure using experimental malaria. To this end, we infected OT-I mice with a transgenic
P. berghei
ANKA strain that expresses ovalbumin (PbTG), which enables the characterization of antigen-specific CD8
+
T cell responses. We then compared antigen-specific CD8
+
T cell populations expressing different levels of the co-inhibitory molecules. High expression of LAG-3 correlated with high expression of PD-1, TIGIT, TIM-3 and CTLA-4. Contrary to what has been described during chronic antigen exposure, antigen-specific CD8
+
T cells with the highest expression of LAG-3 appeared to be fully functional during acute malaria. We evaluated this by measuring IFN-γ, Granzyme B and Perforin production and confirmed the results by employing a newly developed T cell cytotoxicity assay. We found that LAG-3
high
CD8
+
T cells are more cytotoxic than LAG-3
low
or activated but LAG-3
neg
CD8
+
T cells. In conclusion, our data imply that expression of co-inhibitory molecules in acute malaria is not necessarily associated with functional exhaustion but may be associated with an overwhelming T cell activation. Taken together, our findings shed new light on the induction of co-inhibitory molecules during acute T cell activation with ramifications for immunomodulatory therapies targeting these molecules in acute infectious diseases.
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The application of programmed cell death protein 1 (PD-1) antibodies has brought great benefits to non-small cell lung cancer (NSCLC) patients. Nevertheless, not all patients respond ...to anti-PD-1 immunotherapy. This study aimed to find response markers to predict efficacy of anti-PD-1 immunotherapy in NSCLC patients. 80 patients with NSCLC who would accept anti-PD-1 immunotherapy were recruited, and peripheral blood was obtained before and after treatment. Flow cytometry was used to detect proportions of circulating cell subsets and expression of co-stimulatory molecules, co-inhibitory molecules and cytokines in T cells from pre- and post-treatment patients. Results showed that proportions of CD4+ and CD8+ T cells, NK, γδT and mucosal-associated invariant T (MAIT) cells were higher and regulatory T cells (Tregs) were lower in responders (n = 50) after treatment but no obvious difference was found in non-responders (n = 30). After treatment, responders showed an increase in the frequency of co-stimulatory and co-inhibitory molecules, as well as the production of cytokines in T cells. This study indicates that monitoring the alterations of immune markers in circulating cells from NSCLC patients may be helpful to discriminate responders and non-responders, which provides a potential novel way to assess efficacy of anti-PD-1 immunotherapy.
Dendritic cells (DC) are sentinels of immunity, essential for homeostasis of T cell-dependent immune responses. Both functions of DC, initiation of antigen-specific T cell immunity and maintenance of ...tissue-specific tolerance originate from distinct stages of differentiation, immunogenic versus tolerogenic. Dependent on local micro milieu and inflammatory stimuli, tissue resident immature DC with functional plasticity differentiate into tolerogenic or immunogenic DC with stable phenotypes. They efficiently link innate and adaptive immunity and are ideally positioned to modify T cell-mediated immune responses. Since the T cell stimulatory properties of DC are significantly influenced by their expression of signal II ligands, it is critical to understand the impact of distinct costimulatory pathways on DC function. This review gives an overview of functional different human DC subsets with unique profiles of costimulatory molecules and outlines how different costimulatory pathways together with the immunosuppressive cytokine IL-10 bias immunogenic versus tolerogenic DC functions. Furthermore, we exemplarily describe protocols for the generation of two well-defined monocyte-derived DC subsets for their clinical use, immunogenic versus tolerogenic.
IFN-γ plays a crucial role in resisting intracellular parasitic protozoa, such as Eimeria species. In our previous study, we identified 4 molecules derived from Eimeria maxima (E. maxima) that ...significantly inhibited IFN-γ production. However, the mechanism underlying this inhibitory effect remains unknown. In this study, we first investigated the effects of these 4 IFN-γ inhibitory molecules on the expression levels of chicken Toll-like receptors (chTLRs), IL-12, IL-10, TGF-β, and TNF-α in chicken macrophage HD11 and bone marrow-derived dendritic cells (BMDCs). The results demonstrated that these 4 inhibitory molecules significantly downregulated the mRNA levels of chTLR-2, chTLR-4, chTLR-21, and both mRNA and protein levels of IL-12. Subsequently, to clarify the effects of these 4 inhibitory molecules on the IL-12 secretion-related signaling pathways in chicken macrophages, qRT-PCR and Western blot were used to detect the changes of key molecules involved in the signaling pathways of IL-12 secretion (NF-κB, ERK1/2, p38, JNK, STAT3) following coincubation with these inhibitory molecules. Finally, RNAi was employed to verify the function of key molecules in the signaling pathway. The results revealed a significant upregulation in the expression of ERK1/2 phosphorylated protein induced by the 4 inhibitory molecules. Knockdown of the ERK1/2 gene significantly reduced the inhibitory effect of the 4 E. maxima inhibitory molecules on IL-12. These findings indicate that the 4 inhibitory molecules can inhibit the secretion of IL-12 by upregulating the expression of ERK1/2 phosphorylated protein, which is a key molecule in the ERK-MAPK pathway. Our study may contribute to elucidating the mechanisms underlying immune evasion during E. maxima infections, thereby providing new insights for the control of chicken coccidiosis.
Summary
Autoimmune hepatitis (AIH) is characterized by overwhelming effector immune responses associated with defective regulatory T cells (Tregs). Several lines of evidence indicate CD4 as the main ...effectors involved in autoimmune liver damage. Herein we investigate the in‐vitro effects of prednisolone, 6‐mercaptopurine, cyclosporin, tacrolimus, mycophenolic acid (MPA) and rapamycin, immunosuppressive drugs (ISDs) used in AIH treatment, on the expression of proinflammatory cytokines, co‐inhibitory molecules and ability to proliferate of CD4+CD25– cells, isolated from the peripheral blood of treatment‐naive patients with AIH. We note that in healthy subjects (HS) following polyclonal stimulation and in the absence of ISDs, the expression of interferon (IFN)‐γ, interleukin (IL)‐17 and tumour necrosis factor (TNF)‐α by CD4 effectors peaks at 48 h and decreases at 96 h to reach baseline levels. In contrast, in AIH the expression of all these proinflammatory cytokines continue rising between 48 and 96 h. Levels of programmed cell death‐1 (PD‐1), T cell immunoglobulin and mucin domain‐containing molecule‐3 (TIM‐3) and cytotoxic T lymphocyte antigen‐4 (CTLA‐4) increase over 96‐h culture both in HS and AIH, although with faster kinetics in the latter. Exposure to ISDs contains IFN‐γ and PD‐1 expression in AIH, where control over CD4+CD25– cell proliferation is also noted upon exposure to MPA. Treatment with tacrolimus and cyclosporin render CD4+CD25– cells more susceptible to Treg control. Collectively, our data indicate that in treatment‐naive patients with AIH, all ISDs restrain T helper type 1 (Th1) cells and modulate PD‐1 expression. Furthermore, they suggest that tacrolimus and cyclosporin may ameliorate effector cell responsiveness to Tregs.
In this study we investigate the in vitro effects of prednisolone, 6‐MP, cyclosporine, tacrolimus, MPA and rapamycin – immunosuppressive drugs normally used in the treatment of autoimmune hepatitis (AIH) – on the functional phenotype of peripheral blood‐derived CD4 effectors. We report that in treatment‐naïve patients with AIH, all immunosuppressive drugs restrain Th1 immunity and modulate PD1 expression. Our data also suggest that tacrolimus and cyclosporine may ameliorate effector cell responsiveness to regulatory T cells.
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