A peptide tetramer Tk-tPN induces tolerance of cardiac allografting by conversion of type 1 to type 2 immune responses via the Toll-like receptor 2 signal-promoted activation of theMCP1gene

We have shown that type 2 diabetic Goto-Kakizaki (GK) rats develop cerebrovascular endothelial dysfunction, impaired cerebral blood flow (CBF) and mild cognitive deficits. It is increasingly recognized that vascular cognitive impairment may be a new complication of the disease in both type 1 and type 2 diabetes. Toll-like receptor-2 (TLR2) plays a role in cardiovascular complications of diabetes but its involvement in diabetic cerebrovascular disease is unknown. Since brain function heavily depends on constant perfusion, and decreased CBF precedes development of inflammation and cognitive deficits, we hypothesized that enhanced TLR2 signaling in both type 1 and 2 diabetes would contribute to cerebrovascular dysfunction and decreased CBF. Endothelium-dependent relaxation was assessed by measuring acetylcholine (ACh, 10-9 -10-4 M) induced dilatory response in basilar arteries from GK rats in the presence and absence of an anti-TLR2 (1μg) antibody. Vascular contractility to serotonin (10-9 -10-5 M) stimulation was also assessed. Area under the curve (AUC) and maximal effective concentration (Emax as % of max KCl response) were calculated as indices of total relaxation and total contraction, respectively. Basilar artery relaxation was significantly improved in the vessels preincubated (30’) with antiTLR2 (184.8± 24.0 vs. 87.7± 4, p =0.007). The EMax in response to serotonin stimulation in the anti-TLR2 treated vessels was not significantly different than the vessels from the untreated diabetic GK rats (110.6± 4.9% vs 99.4.±4.5%). To further assess the in vivo functional effects of TLR2 signaling, CBF (relative intensity) was measured using laser speckle imaging in wild type and TLR2-knockout (KO) mice using an STZ induced diabetes model. Six weeks after induction of diabetes, wild-type diabetic mice exhibited a significant decrease in CBF vs. control (210±22.5 vs. 300.3±18.4, p<0.05). This decrease in cerebral perfusion was attenuated in the TLR2-KO diabetic mice compared to TLR2 KO control (322.6±10.1 vs. 344. 5±11. 04). These findings suggest that TLR2 signaling leads to vascular dysfunction through decreased endothelium dependent relaxation, and could contribute to decreased CBF in diabetes predisposing to vascular cognitive impairment.

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

Science Signaling ◽

10.1126/scisignal.abe1757 ◽

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.

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Faculty Opinions recommendation of NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1019900.238431 ◽

2004 ◽

Author(s):

Maria Rescigno

Keyword(s):

Negative Regulator ◽

Toll Like Receptor ◽

T Helper ◽

Toll Like Receptor 2 ◽

Helper Type

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Differential Activation of CD8+Tumor-Specific Tc1 and Tc2 Cells by an IL-10-Producing Murine Plasmacytoma

Developmental Immunology ◽

10.1155/1998/93545 ◽

1998 ◽

Vol 6 (3-4) ◽

pp. 331-342 ◽

Cited By ~ 1

Author(s):

Christoph Specht ◽

Hans-Gerd Pauels ◽

Christian Becker ◽

Eckehart Kölsch

Keyword(s):

T Cells ◽

Immune Responses ◽

Tumor Cells ◽

T Cell Subsets ◽

Early Stages ◽

Specific Tolerance

The involvement of counteractiveCD8+T-cell subsets during tumor-specific immune responses was analyzed in a syngeneic murine plasmacytoma model.CD8+Tc cells against the immunogenic IL-10-producing BALB/c plasmacytoma ADJ-PC-5 can be easily induced by immunization of BALB/c mice with X-irradiated ADJ-PC-5 tumor cellsin vivoandin vitro. However, the failure of recipient mice to mount a protective Tc response against the tumor during early stages of a real or simulated tumor growth is not due to immunological ignorance, but depends on the induction of tumor-specific tolerance, involving a population of tumorinducedCD8+T cells that are able to inhibit the generation of tumor-specific Tc cells in a primary ADJ-PC-5-specific MLTC, using IFN-γas a suppressive factor. Whereas most longterm cultivated CD8+ADJ-PC-5-specific Tc lines produce type-1 cytokines on stimulation, at least two of them, which were derived from a primary MLTC, display a type-2 cytokine spectrum. Furthermore, the primaryin vitroTc response against ADJ-PC-5 cells shows characteristics of a Tc2 response. The Tc response is strictly depending on tumor-derived IL-10.CD8+Tc cells that are induced in a primary MLTC do not produce IFN-γ, and the tumor-specific Tc response is enhanced by IL-4 but suppressed by IFN-γor IL-12. In contrast, ADJ-PC- 5-specificCD8+Tc cells from immunized mice are IFN-γproducing Tc1 cells. Since the primaryin vitroTc response against the tumor is suppressed even by the smallest numbers of irradiated ADJ-PC-5-specific Tc1 cells via IFN-γthese Tc1 cells behave similar to the suppressiveCD8+T cells that are induced during early stages of ADJ-PC-5 tumorigenesis.

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