scholarly journals A protein associated with Toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses

2007 ◽  
Vol 204 (12) ◽  
pp. 2963-2976 ◽  
Author(s):  
Koichiro Takahashi ◽  
Takuma Shibata ◽  
Sachiko Akashi-Takamura ◽  
Takashi Kiyokawa ◽  
Yasutaka Wakabayashi ◽  
...  
Keyword(s):  
Cell Surface ◽  
Immune Responses ◽  
Poly I:C ◽  
Toll Like Receptor ◽  
T Helper ◽  
Surface Molecules ◽  
Adaptive Immune ◽  
And Function ◽  
Tlr3 Ligand Poly

Immune cells express multiple Toll-like receptors (TLRs) that are concomitantly activated by a variety of pathogen products. Although there is presumably a need to coordinate the expression and function of TLRs in individual cells, little is known about the mechanisms governing this process. We show that a protein associated with TLR4 (PRAT4A) is required for multiple TLR responses. PRAT4A resides in the endoplasmic reticulum, and PRAT4A knockdown inhibited trafficking of TLR1 and TLR4 to the cell surface and ligand-induced trafficking of TLR9 to lysosomes. Other cell-surface molecules were expressed normally on immunocytes from PRAT4A−/− mice. There was impaired cytokine production to TLR ligands, except to the TLR3 ligand poly(I:C), and to whole bacteria. Activation of antigen-specific T helper type 1 responses were also defective. Moreover, PRAT4A−/− bone marrow chimeric mice were resistant to lipopolysaccharide-induced sepsis. These results suggest that PRAT4A regulates the subcellular distribution and response of multiple TLRs and is required for both innate and adaptive immune responses.

scholarly journals The IL4I1 Enzyme: A New Player in the Immunosuppressive Tumor Microenvironment

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 757 ◽  
Author(s):  
Valérie Molinier-Frenkel ◽  
Armelle Prévost-Blondel ◽  
Flavia Castellano
Keyword(s):  
Tumor Microenvironment ◽  
Immune Responses ◽  
Essential Amino Acids ◽  
T Helper ◽  
Preclinical Models ◽  
Adaptive Immune ◽  
Immunosuppressive Tumor Microenvironment ◽  
Fine Control ◽  
Antigen Presenting

The high metabolic needs of T lymphocytes in response to activation make them particularly vulnerable to modifications of their biochemical milieu. Immunosuppressive enzymes produced in the tumor microenvironment modify nutrient availability by catabolizing essential or semi-essential amino acids and producing toxic catabolites, thus participating in the local sabotage of the antitumor immune response. L-amino-acid oxidases are FAD-bound enzymes found throughout evolution, from bacteria to mammals, and are often endowed with anti-infectious properties. IL4I1 is a secreted L-phenylalanine oxidase mainly produced by inflammatory antigen-presenting cells—in particular, macrophages present in T helper type 1 granulomas and in various types of tumors. In the last decade, it has been shown that IL4I1 is involved in the fine control of B- and T-cell adaptive immune responses. Preclinical models have revealed its role in cancer immune evasion. Recent clinical data highlight IL4I1 as a new potential prognostic marker in human melanoma. As a secreted enzyme, IL4I1 may represent an easily targetable molecule for cancer immunotherapy.

scholarly journals Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2–MyD88 signal pathway in dendritic cells and enhances Th2 immune responses

2008 ◽  
Vol 205 (1) ◽  
pp. 79-90 ◽  
Author(s):  
De Yang ◽  
Qian Chen ◽  
Shao Bo Su ◽  
Ping Zhang ◽  
Kahori Kurosaka ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Adaptive Immune System ◽  
Secretory Protein ◽  
Myeloid Differentiation ◽  
Toll Like Receptor ◽  
T Helper ◽  
Adaptive Immune ◽  
Eosinophil Granule ◽  
Myeloid Differentiation Factor

Eosinophil-derived neurotoxin (EDN) is an eosinophil granule–derived secretory protein with ribonuclease and antiviral activity. We have previously shown that EDN can induce the migration and maturation of dendritic cells (DCs). Here, we report that EDN can activate myeloid DCs by triggering the Toll-like receptor (TLR)2–myeloid differentiation factor 88 signaling pathway, thus establishing EDN as an endogenous ligand of TLR2. EDN activates TLR2 independently of TLR1 or TLR6. When mice were immunized with ovalbumin (OVA) together with EDN or with EDN-treated OVA-loaded DCs, EDN enhanced OVA-specific T helper (Th)2-biased immune responses as indicated by predominant production of OVA-specific interleukin (IL)-5, IL-6, IL-10, and IL-13, as well as higher levels of immunoglobulin (Ig)G1 than IgG2a. Based on its ability to serve as a chemoattractant and activator of DCs, as well as the capacity to enhance antigen-specific immune responses, we consider EDN to have the properties of an endogenous alarmin that alerts the adaptive immune system for preferential enhancement of antigen-specific Th2 immune responses.

scholarly journals Synergistic Effect of Nod1 and Nod2 Agonists with Toll-Like Receptor Agonists on Human Dendritic Cells To Generate Interleukin-12 and T Helper Type 1 Cells

2005 ◽  
Vol 73 (12) ◽  
pp. 7967-7976 ◽  
Author(s):  
Hiroyuki Tada ◽  
Setsuya Aiba ◽  
Ken-Ichiro Shibata ◽  
Toshiaki Ohteki ◽  
Haruhiko Takada
Keyword(s):  
Lipid A ◽  
Poly I:C ◽  
Interleukin 12 ◽  
Toll Like Receptor ◽  
T Helper ◽  
Cpg Dna ◽  
Tlr Agonists ◽  
Ifn Γ ◽  
Culture Supernatants

ABSTRACT A synthetic Nod2 agonist, muramyldipeptide (MDP), and two Nod1 agonists, FK565 and FK156, mimic the bacterial peptidoglycan moiety and are powerful adjuvants that induce cell-mediated immunity, especially delayed-type hypersensitivity. In this study, we used human dendritic cell (DC) cultures to examine possible T helper type 1 (Th1) responses induced by MDP and FK565/156 in combination with various synthetic Toll-like receptor (TLR) agonists, including synthetic lipid A (TLR4 agonist), the synthetic triacyl lipopeptide Pam3CSSNA (TLR2 agonist), poly(I:C) (TLR3 agonist), and CpG DNA (TLR9 agonist). Immature DCs derived from human monocytes expressed mRNAs for Nod1, Nod2, TLR2, TLR3, TLR4, and TLR9. The stimulation of DCs with MDP and FK565 in combination with lipid A, poly(I:C), and CpG DNA, but not with Pam3CSSNA, synergistically induced interleukin-12 (IL-12) p70 and gamma interferon (IFN-γ), but not IL-18, in culture supernatants and induced IL-15 on the cell surface. In correlation with the cytokine induction, an upregulation of the mRNA expression of these cytokine genes was observed. Notably, IL-12 p35 mRNA expression increased >1,000-fold upon stimulation with lipid A plus either MDP or FK565 compared with stimulation with each stimulant alone. In contrast, for the expression of CD83 and costimulatory molecules such as CD40, CD80, and CD86, no synergistic effects were observed upon stimulation with Nod plus TLR agonists. The culture supernatants of DCs stimulated with lipid A plus either MDP or FK565 activated human T cells to produce high levels of IFN-γ, and the activity was attributable to DC-derived IL-12. These findings suggest that Nod1 and Nod2 agonists in combination with TLR3, TLR4, and TLR9 agonists synergistically induce IL-12 and IFN-γ production in DCs to induce Th1-lineage immune responses.

Select hyperactivating NLRP3 ligands enhance the TH1- and TH17-inducing potential of human type 2 conventional dendritic cells

2021 ◽  
Vol 14 (680) ◽  
pp. eabe1757
Author(s):  
Lukas Hatscher ◽  
Christian H. K. Lehmann ◽  
Ariawan Purbojo ◽  
Constantin Onderka ◽  
Chunguang Liang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Vaccine Development ◽  
Inflammatory Diseases ◽  
Toll Like Receptor ◽  
T Helper ◽  
Conventional Type ◽  
Prime Target

The detection of microorganisms and danger signals by pattern recognition receptors on dendritic cells (DCs) and the consequent formation of inflammasomes are pivotal for initiating protective immune responses. Although the activation of inflammasomes leading to secretion of the cytokine IL-1β is typically accompanied by pyroptosis (an inflammatory form of lytic programmed cell death), some cells can survive and exist in a state of hyperactivation. Here, we found that the conventional type 2 DC (cDC2) subset is the major human DC subset that is transcriptionally and functionally poised for inflammasome formation and response without pyroptosis. When cDC2 were stimulated with ligands that relatively weakly activated the inflammasome, the cells did not enter pyroptosis but instead secreted IL-12 family cytokines and IL-1β. These cytokines induced prominent T helper type 1 (TH1) and TH17 responses that were superior to those seen in response to Toll-like receptor (TLR) stimulation alone or to stronger, classical inflammasome ligands. These findings not only define the human cDC2 subpopulation as a prime target for the treatment of inflammasome-dependent inflammatory diseases but may also inform new approaches for adjuvant and vaccine development.

Understanding the increased risk of infections in diabetes: innate and adaptive immune responses in type 1 diabetes

Metabolism ◽  
2021 ◽  
pp. 154795
Author(s):  
Anna W.M. Janssen ◽  
Rinke Stienstra ◽  
Martin Jaeger ◽  
Alain J. van Gool ◽  
Leo A.B. Joosten ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Immune Responses ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Increased Risk

scholarly journals The 3′ CCACCA Sequence of tRNAAla(UGC) Is the Motif That Is Important in Inducing Th1-Like Immune Response, and This Motif Can Be Recognized by Toll-Like Receptor 3

2006 ◽  
Vol 13 (7) ◽  
pp. 733-739 ◽  
Author(s):  
Zhijun Wang ◽  
Li Xiang ◽  
Junjie Shao ◽  
Zhenghong Yuan
Keyword(s):  
Immune Responses ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Hepatitis B Surface Antigen ◽  
Toll Like Receptor ◽  
Anticodon Loop ◽  
T Helper ◽  
D Loop ◽  
Th 1 ◽  
Ctl Responses

ABSTRACT In this article, the immunogenicity of tRNA and the recognition of tRNA by Toll-like receptors (TLRs) are analyzed. Analyses of the effects of different tRNAAla(UGC) fragments (tRNAAla1-76 [corresponding to positions 1 through 76], tRNAAla26-76, tRNAAla40-76, tRNAAla62-76, tRNAAla1-70, tRNAAla26-70, tRNAAla40-70, and tRNAAla62-70) on the immune responses of hepatitis B surface antigen (HBsAg) were performed with BALB/c mice. Results show that tRNAAla1-76, tRNAAla26-76, tRNAAla40-76, and tRNAAla62-76 adjuvants not only induced stronger T helper (Th) 1 immune responses but also cytotoxic-T-lymphocyte (CTL) responses relative to tRNAAla1-70, tRNAAla26-70, tRNAAla40-70, and tRNAAla62-70 adjuvants in HBsAg immunization. A deletion of the D loop (tRNAAla26-76), anticodon loop (tRNAAla40-76), or TψC (tRNAAla62-76) loop of tRNAAla(UGC) does not significantly decrease the adjuvant characteristic of tRNAAla(UGC). However a deletion of the 3′-end CCACCA sequence (tRNAAla1-70, tRNAAla26-70, tRNAAla40-70, and tRNAAla62-70) of tRNAAla(UGC) significantly decreased the adjuvant characteristic in Th1 and CTL immune responses. Moreover, the recognitions of different tRNAAla(UGC) fragments by TLR3, TLR7, TLR8, and TLR9 were analyzed. Results show that a deletion of the 3′ CCACCA sequence of tRNAAla(UGC) significantly decreased the recognition by TLR3. We concluded that the 3′ CCACCA sequence of tRNAAla(UGC) is the important motif to induce Th1 and CTL responses and this motif can be effectively recognized by TLR3.

Sign in / Sign up

Export Citation Format

Share Document