R-Ras is required for murine dendritic cell maturation and CD4+ T-cell priming

Abstract R-Ras is a member of the RAS superfamily of small GTP-binding proteins. The physiologic function of R-Ras has not been fully elucidated. We found that R-Ras is expressed by lymphoid and nonlymphoid tissues and drastically up-regulated when bone marrow progenitors are induced to differentiate into dendritic cells (DCs). To address the role of R-Ras in DC functions, we generated a R-Ras-deficient mouse strain. We found that tumors induced in Rras−/− mice formed with shorter latency and attained greater tumor volumes. This finding has prompted the investigation of a role for R-Ras in the immune system. Indeed, Rras−/− mice were impaired in their ability to prime allogeneic and antigen-specific T-cell responses. Rras−/− DCs expressed lower levels of surface MHC class II and CD86 in response to lipopolysaccharide compared with wild-type DCs. This was correlated with a reduced phosphorylation of p38 and Akt. Consistently, R-Ras–GTP level was increased within 10 minutes of lipopolysaccharide stimulation. Furthermore, Rras−/− DCs have attenuated capacity to spread on fibronectin and form stable immunologic synapses with T cells. Altogether, these findings provide the first demonstration of a role for R-Ras in cell-mediated immunity and further expand on the complexity of small G-protein signaling in DCs.

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An ancient motif unique for human STING, RGS12 and SARS-CoV-2 spike proteins

10.21203/rs.3.rs-132824/v2 ◽

2021 ◽

Author(s):

Suleyman Aydin ◽

Ayca Cakmak Aydin

Keyword(s):

T Cell ◽

Molecular Mimicry ◽

Direct Interaction ◽

Spike Protein ◽

G Protein Signaling ◽

Beta Lactamase ◽

T Cell Exhaustion ◽

Protein Signaling ◽

Cell Exhaustion

Abstract The coronavirus named as SARS-CoV-2 is the cause of the COVID-19 pandemic and spreading rapidly1. It is a pneumonia outbreak2 with T cell exhaustion, cytokine storm and coagulation3,4. Short motifs on proteins play important roles on protein-protein interactions5,6. We hypothetized role of molecular mimicry of small-xxx-small motifs for the spike protein of SARS-CoV-2. Here we show that a unique and evolutionary conserved motif is found only on the spike protein of SARS-CoV-2 and stimulator of interferon genes (STING) proteins. Surprisingly we could not find this motif on any other protein of any living form. We found a similar, but not identical motif mimicry for the spike and regulator of G protein signaling 12 (RGS12), C1QT4 and also for proteins of Archaea and beta-lactamase enzymes of bacteria including Mycobacterium tuberculosis. STING proteins have roles on coagulation, T cell exhaustion, cytokine release1-3 and RGS12 on inflammation7. In contrast to cGAS-STING pathway8, the motif mimicry indicated a direct interaction between spike and STING proteins suggesting the importance of STING, RGS12 and C1QT4 on the pathogenesis of COVID-19. To our surprise, the molecular mimicry showed that beta-lactamase inhibitors may be effective against SARS-CoV-2. The motif is unique, as found on Archaea and Cnidaria it is evolutionary old but a new target and mechanism for the COVID-19.

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The endless race betweenTrypanosoma cruziand host immunity: lessons for and beyond Chagas disease

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399410001560 ◽

2010 ◽

Vol 12 ◽

Cited By ~ 111

Author(s):

Caroline Junqueira ◽

Braulia Caetano ◽

Daniella C. Bartholomeu ◽

Mariane B. Melo ◽

Catherine Ropert ◽

...

Keyword(s):

T Cell ◽

Chagas Disease ◽

Protozoan Parasite ◽

Genetically Engineered ◽

Disease Outcome ◽

Host Responses ◽

Cell Mediated Immunity ◽

Cell Responses ◽

Host Parasite

Infection with the protozoan parasiteTrypanosoma cruzi, the agent of Chagas disease, is characterised by a variable clinical course – from symptomless cases to severe chronic disease with cardiac and/or gastrointestinal involvement. The variability in disease outcome has been attributed to host responses as well as parasite heterogeneity. In this article, we review studies indicating the importance of immune responses as key determinants of host resistance toT. cruziinfection and the pathogenesis of Chagas disease. Particular attention is given to recent studies defining the role of cognate innate immune receptors and immunodominant CD8+T cells that recognise parasite components – both crucial for host–parasite interaction and disease outcome. In light of these studies we speculate about parasite strategies that induce a strong and long-lasting T-cell-mediated immunity but at the same time allow persistence of the parasite in the vertebrate host. We also discuss what we have learned from these studies for increasing our understanding of Chagas pathogenesis and for the design of new strategies to prevent the development of Chagas disease. Finally, we highlight recent studies employing a genetically engineered attenuatedT. cruzistrain as a vaccine shuttle that elicits potent T cell responses specific to a tumour antigen and protective immunity against a syngeneic melanoma cell line.

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Small G Protein Signaling in Neuronal Plasticity and Memory Formation: The Specific Role of Ras Family Proteins

Neuron ◽

10.1016/j.neuron.2010.09.013 ◽

2010 ◽

Vol 68 (3) ◽

pp. 340-361 ◽

Cited By ~ 76

Author(s):

Xiaojing Ye ◽

Thomas J. Carew

Keyword(s):

G Protein ◽

Neuronal Plasticity ◽

Memory Formation ◽

Specific Role ◽

G Protein Signaling ◽

Protein Signaling ◽

Small G Protein ◽

Ras Family ◽

Ras Family Proteins

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An ancient motif unique for human STING, RGS12 and SARS-CoV-2 spike proteins

10.21203/rs.3.rs-132824/v1 ◽

2020 ◽

Author(s):

Suleyman Aydin ◽

Ayca Cakmak Aydin

Keyword(s):

T Cell ◽

Molecular Mimicry ◽

Direct Interaction ◽

Spike Protein ◽

G Protein Signaling ◽

Beta Lactamase ◽

T Cell Exhaustion ◽

Protein Signaling ◽

Cell Exhaustion

Abstract The coronavirus named as SARS-CoV-2 is the cause of the COVID-19 pandemic and spreading rapidly1. It is a pneumonia outbreak2 with T cell exhaustion, cytokine storm and coagulation3,4. Short motifs on proteins play important roles on protein-protein interactions5,6. We hypothetized role of molecular mimicry of small-xxx-small motifs for the spike protein of SARS-CoV-2. Here we show that a unique and evolutionary conserved motif is found only on the spike protein of SARS-CoV-2 and stimulator of interferon genes (STING) proteins. Surprisingly we could not find this motif on any other protein of any living form. We found a similar, but not identical motif mimicry for the spike and regulator of G protein signaling 12 (RGS12), C1QT4 and also for proteins of Archaea and beta-lactamase enzymes of bacteria including Mycobacterium tuberculosis. STING proteins have roles on coagulation, T cell exhaustion, cytokine release1-3 and RGS12 on inflammation7. In contrast to cGAS-STING pathway8, the motif mimicry indicated a direct interaction between spike and STING proteins suggesting the importance of STING, RGS12 and C1QT4 on the pathogenesis of COVID-19. To our surprise, the molecular mimicry showed that beta-lactamase inhbitors may be effective against SARS-CoV-2. The motif is unique, as found on Archaea and Cnidaria it is evolutionary old but a new target and mechanism for the COVID-19.

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Faculty Opinions recommendation of Peptide-MHC class II dimers as therapeutics to modulate antigen-specific T cell responses in autoimmune diabetes.

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

10.3410/f.1016402.200705 ◽

2003 ◽

Author(s):

Matthias von Herrath

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

Autoimmune Diabetes ◽

T Cell Responses ◽

Class Ii ◽

Cell Responses

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Faculty Opinions recommendation of Durable protection of rhesus macaques immunized with a replicating adenovirus-SIV multigene prime/protein boost vaccine regimen against a second SIVmac251 rectal challenge: role of SIV-specific CD8+ T cell responses.

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

10.3410/f.1047136.498191 ◽

2006 ◽

Author(s):

Kendall Smith

Keyword(s):

T Cell ◽

Rhesus Macaques ◽

T Cell Responses ◽

Cd8 T Cell ◽

Vaccine Regimen ◽

Cell Responses ◽

Protein Boost ◽

Boost Vaccine

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Faculty Opinions recommendation of Cutting edge: Conditional MHC class II expression reveals a limited role for B cell antigen presentation in primary and secondary CD4 T cell responses.

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

10.3410/f.718020496.793480946 ◽

2013 ◽

Author(s):

Tim Manser

Keyword(s):

T Cell ◽

B Cell ◽

Antigen Presentation ◽

Mhc Class Ii ◽

T Cell Responses ◽

Class Ii ◽

Cutting Edge ◽

Cd4 T Cell ◽

Cell Antigen ◽

Cell Responses

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T cell–specific STAT3 deficiency abrogates lupus nephritis

Lupus ◽

10.1177/0961203319877242 ◽

2019 ◽

Vol 28 (12) ◽

pp. 1468-1472 ◽

Cited By ~ 2

Author(s):

N Yoshida ◽

F He ◽

V C Kyttaris

Keyword(s):

T Cells ◽

T Cell ◽

Lupus Nephritis ◽

Lupus Erythematosus ◽

Cell Responses ◽

Cytokines And Chemokines ◽

Novel Approach ◽

Cell Tissue ◽

External Stimuli

Signal transducer and activator of transcription (STAT) 3 is a regulator of T-cell responses to external stimuli, such as pro-inflammatory cytokines and chemokines. We have previously shown that STAT3 is activated (phosphorylated) at high levels in systemic lupus erythematosus (SLE) T cells and mediates chemokine-induced migration and T:B cell interactions. Stattic, a small molecular STAT3 inhibitor, can partially ameliorate lupus nephritis in mice. To understand the role of STAT3 better in T-cell pathophysiology in lupus nephritis and its potential as a treatment target, we silenced its expression in T cells using a cd4-driven CRE-Flox model. We found that lupus-prone mice that do not express STAT3 in T cells did not develop lymphadenopathy, splenomegaly, or glomerulonephritis. Moreover, the production of anti-dsDNA antibodies was decreased in these mice compared to controls. To dissect the mechanism, we also used a nephrotoxic serum model of nephritis. In this model, T cell–specific silencing of STAT3 resulted in amelioration of nephrotoxic serum-induced kidney damage. Taken together, our results suggest that in mouse models of autoimmune nephritis, T cell–specific silencing of STAT3 can hamper their ability to help B cells to produce autoantibodies and induce cell tissue infiltration. We propose that STAT3 inhibition in T cells represents a novel approach in the treatment of SLE and lupus nephritis in particular.

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