scholarly journals T cell-intrinsic role for Nod2 in protection against Th17-mediated uveitis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Ruth J. Napier ◽  
Ellen J. Lee ◽  
Michael P. Davey ◽  
Emily E. Vance ◽  
João M. Furtado ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nucleotide Binding ◽  
Inflammatory Disorder ◽  
Blau Syndrome ◽  
Cellular Mechanisms ◽  
Independent Mechanism ◽  
Intrinsic Function ◽  
Oligomerization Domain

Abstract Mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) cause Blau syndrome, an inflammatory disorder characterized by uveitis. The antimicrobial functions of Nod2 are well-established, yet the cellular mechanisms by which dysregulated Nod2 causes uveitis remain unknown. Here, we report a non-conventional, T cell-intrinsic function for Nod2 in suppression of Th17 immunity and experimental uveitis. Reconstitution of lymphopenic hosts with Nod2−/− CD4+ T cells or retina-specific autoreactive CD4+ T cells lacking Nod2 reveals a T cell-autonomous, Rip2-independent mechanism for Nod2 in uveitis. In naive animals, Nod2 operates downstream of TCR ligation to suppress activation of memory CD4+ T cells that associate with an autoreactive-like profile involving IL-17 and Ccr7. Interestingly, CD4+ T cells from two Blau syndrome patients show elevated IL-17 and increased CCR7. Our data define Nod2 as a T cell-intrinsic rheostat of Th17 immunity, and open new avenues for T cell-based therapies for Nod2-associated disorders such as Blau syndrome.

scholarly journals B220+Double-Negative T Cells Suppress Polyclonal T Cell Activation by a Fas-Independent Mechanism That Involves Inhibition of IL-2 Production

2003 ◽  
Vol 171 (5) ◽  
pp. 2421-2426 ◽  
Author(s):  
Abdel Rahim A. Hamad ◽  
Abdiaziz S. Mohamood ◽  
Crystal J. Trujillo ◽  
Ching-Tai Huang ◽  
Emily Yuan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Double Negative ◽  
Independent Mechanism ◽  
Double Negative T Cells

Mutational analysis of human NOD1 and NOD2 NACHT domains reveals different modes of activation

2011 ◽  
Vol 18 (1) ◽  
pp. 100-111 ◽  
Author(s):  
Birte Zurek ◽  
Martina Proell ◽  
Roland N Wagner ◽  
Robert Schwarzenbacher ◽  
Thomas A Kufer
Keyword(s):  
Atp Hydrolysis ◽  
Mutational Analysis ◽  
Inflammatory Diseases ◽  
Nucleotide Binding ◽  
Blau Syndrome ◽  
Innate Immune Responses ◽  
Atpase Domain ◽  
Early Onset Sarcoidosis ◽  
Key Residues ◽  
Oligomerization Domain

Nucleotide-binding oligomerization domain-containing protein (NOD)1 and NOD2 are intracellular pattern recognition receptors (PRRs) of the nucleotide-binding domain and leucine-rich repeat containing (NLR) gene family involved in innate immune responses. Their centrally located NACHT domain displays ATPase activity and is necessary for activation and oligomerization leading to inflammatory signaling responses. Mutations affecting key residues of the ATPase domain of NOD2 are linked to severe auto-inflammatory diseases, such as Blau syndrome and early-onset sarcoidosis. By mutational dissection of the ATPase domain function, we show that the NLR-specific extended Walker B box (DGhDE) can functionally replace the canonical Walker B sequence (DDhWD) found in other ATPases. A requirement for an intact Walker A box and the magnesium-co-ordinating aspartate of the classical Walker B box suggest that an initial ATP hydrolysis step is necessary for activation of both NOD1 and NOD2. In contrast, a Blau-syndrome associated mutation located in the extended Walker B box of NOD2 that results in higher autoactivation and ligand-induced signaling does not affect NOD1 function. Moreover, mutation of a conserved histidine in the NACHT domain also has contrasting effects on NOD1 and NOD2 mediated NF-κB activation. We conclude that these two NLRs employ different modes of activation and propose distinct models for activation of NOD1 and NOD2.

scholarly journals Blau syndrome associated with nucleotide-binding oligomerization domain containing 2 mutation in a baby from Malaysia

2019 ◽  
Vol 64 (5) ◽  
pp. 400
Author(s):  
ZachariasAloysius Dwi Pramono ◽  
KinFon Leong ◽  
Reiko Sato ◽  
GlendaGuek Khim Oh ◽  
Uttam Surana
Keyword(s):  
Nucleotide Binding ◽  
Blau Syndrome ◽  
Oligomerization Domain

scholarly journals Natural killer T cells in lipoprotein metabolism and atherosclerosis

2011 ◽  
Vol 106 (11) ◽  
pp. 814-819 ◽  
Author(s):  
Godfrey Getz ◽  
Paul VanderLaan ◽  
Catherine Reardon
Keyword(s):  
T Cells ◽  
T Cell ◽  
Natural Killer ◽  
Cell Receptor ◽  
Nkt Cells ◽  
Inflammatory Disorder ◽  
Chronic Inflammatory Disorder ◽  
Invariant Nkt Cells ◽  
Adaptive Immune ◽  
Natural Killer T

SummaryCells of both the innate and adaptive immune system participate in the development of atherosclerosis, a chronic inflammatory disorder of medium and large arteries. Natural killer T (NKT) cells express surface markers characteristic of natural killer cells and conventional T cells and bridge the innate and adaptive immune systems. The development and activation of NKT cells is dependent upon CD1d, a MHC-class I-type molecule that presents lipids, especially glycolipids to the T cell receptors on NKT cells. There are two classes of NKT cells; invariant NKT cells that express a semi-invariant T cell receptor and variant NKT cells. This review summarises studies in murine models in which the effect of the activation, overexpression or deletion of NKT cells or only invariant NKT cells on atherosclerosis has been examined.

scholarly journals Systemic CD4 Immunity as a Key Contributor to PD-L1/PD-1 Blockade Immunotherapy Efficacy

2020 ◽  
Vol 11 ◽  
Author(s):  
Miren Zuazo ◽  
Hugo Arasanz ◽  
Ana Bocanegra ◽  
Gonzalo Fernandez ◽  
Luisa Chocarro ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Strong Predictor ◽  
Cellular Mechanisms ◽  
Lung Cancer Patients ◽  
Helper Function ◽  
Cell Subpopulations ◽  
Cytotoxic Therapies ◽  
T Cell Subpopulations

PD-L1/PD-1 blockade immunotherapy has significantly improved treatment outcome for several cancer types compared to conventional cytotoxic therapies. However, the specific molecular and cellular mechanisms behind its efficacy are currently unclear. There is increasing evidence in murine models and in patients that unveil the key importance of systemic immunity to achieve clinical responses under several types of immunotherapy. Indeed, PD-L1/PD-1 blockade induces the expansion of systemic CD8+ PD-1+ T cell subpopulations which might be responsible for direct anti-tumor responses. However, the role of CD4+ T cells in PD-L1/PD-1 blockade-induced anti-tumor responses has been less documented. In this review we focus on the experimental data supporting the “often suspected” indispensable helper function of CD4 T cells towards CD8 effector anti-tumor responses in cancer; and particularly, we highlight the recently published studies uncovering the key contribution of systemic CD4 T cells to clinical efficacy in PD-L1/PD-1 blockade therapies. We conclude and propose that the presence of specific CD4 T cell memory subsets in peripheral blood before the initiation of treatments is a strong predictor of responses in non-small cell lung cancer patients. Therefore, development of new approaches to improve CD4 responses before PD-L1/PD-1 blockade therapy could be the solution to increase response rates and survival of patients.

scholarly journals The Inflammasome and Caspase-1 Activation: A New Mechanism Underlying Increased Inflammatory Activity in Human Visceral Adipose Tissue

Endocrinology ◽  
2011 ◽  
Vol 152 (10) ◽  
pp. 3769-3778 ◽  
Author(s):  
Tim B. Koenen ◽  
Rinke Stienstra ◽  
Lambertus J. van Tits ◽  
Leo A. B. Joosten ◽  
Jeroen F. van Velzen ◽  
...  
Keyword(s):  
T Cells ◽  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Cd8 T Cells ◽  
Nucleotide Binding ◽  
Caspase 1 ◽  
Pyrin Domain ◽  
Inflammatory Status ◽  
Visceral Adipose ◽  
Oligomerization Domain

The immune competent abdominal adipose tissue, either stored viscerally [visceral adipose tissue (VAT)] or sc [sc adipose tissue (SAT)], has been identified as a source of IL-1β and IL-18. To become active, the proforms of these cytokines require processing by caspase-1, which itself is mediated by the inflammasome. In this descriptive study, we investigate the expression of inflammasome components and caspase-1 in human fat and determine whether caspase-1 activity contributes to the enhanced inflammatory status of VAT. Paired SAT and VAT biopsies from 10 overweight subjects (body mass index, 25–28 kg/m2) were used to study the cellular composition and the intrinsic inflammatory capacity of both adipose tissue depots. The percentage of CD8+ T cells within the lymphocyte fraction was significantly higher in VAT compared with SAT (41.6 vs. 30.4%; P < 0.05). Adipose tissue cultures showed a higher release of IL-1β (10-fold; P < 0.05), IL-18 (3-fold; P < 0.05), and IL-6 and IL-8 (3-fold, P < 0.05; and 4-fold, P < 0.05, respectively) from VAT compared with SAT that was significantly reduced by inhibiting caspase-1 activity. In addition, caspase-1 activity was 3-fold (P < 0.05) higher in VAT compared with SAT, together with an increase in the protein levels of the inflammasome members apoptosis-associated speck-like protein containing a C-terminal caspase-recruitment domain (2-fold; P < 0.05) and nucleotide-binding oligomerization domain- like receptor pyrin domain containing 3 (2-fold; nonsignificant). Finally, caspase-1 activity levels were positively correlated with the percentage of CD8+ T cells present in adipose tissue. Our results show that caspase-1 and nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 inflammasome members are abundantly present in human VAT. The increased intrinsic caspase-1 activity in VAT represents a novel and specific inflammatory pathway that may determine the proinflammatory character of this specific depot.

scholarly journals Evidence for an alpha/beta T cell-independent mechanism of resistance to mycobacteria. Bacillus-Calmette-Guerin causes progressive infection in severe combined immunodeficient mice, but not in nude mice or in mice depleted of CD4+ and CD8+ T cells.

1992 ◽  
Vol 176 (2) ◽  
pp. 581-586 ◽  
Author(s):  
A A Izzo ◽  
R J North
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nude Mice ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Scid Mice ◽  
Bacillus Calmette Guerin ◽  
Mechanism Of Resistance ◽  
Independent Mechanism ◽  
Alpha Beta

Depleting thymectomized mice of CD4+ T cells, or CD4+ plus CD8+ T cells, rendered them incapable of resolving Bacillus-Calmette-Guerin (BCG) infection in their lives, spleens, kidneys, and lungs. However, it did not render them incapable of stabilizing infection in the latter three organs after an initial period of BCG growth. Athymic nude mice showed a similar capacity to control BCG growth in these organs after a certain stage of infection. In contrast, congenitally severe combined immunodeficient (SCID) mice appeared to offer no resistance to BCG infection, in that the organism grew progressively in all organs of these mice and was lethal for them beginning on day 55 of infection. The results suggest that, although CD4+ T cells are important for resolving BCG infection, an alpha/beta T cell-independent mechanism of resistance can be acquired at 2-3 wk of infection that is capable of inhibiting further BCG growth in all organs except the lungs. Because this mechanism is absent from SCID mice, it is likely that it depends on the functions of gamma/delta T cells, B cells, or both types of cells. In keeping with this possibility is the additional finding that SCID mice engrafted with lymph node cells depleted of CD4+ or CD8+ T cells were capable of expressing an appreciable level of resistance against BCG infection.

Regulatory T cell/Th17 balance in the pathogenesis of pediatric Behçet disease

Rheumatology ◽  
2021 ◽  
Author(s):  
Anne Filleron ◽  
Tu Anh Tran ◽  
Audrey Hubert ◽  
Alexia Letierce ◽  
Guillaume Churlaud ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Response ◽  
Behçet Disease ◽  
Inflammatory Disorder ◽  
Behcet Disease ◽  
Regulatory T Lymphocytes ◽  
Hla Dr ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Abstract Objectives Behçet disease (BD) is a chronic systemic inflammatory disorder of unknown aetiology. The aim of this study was to determine the orientation of T cell subpopulations in pediatric BD and more precisely to look for a regulatory T lymphocytes (Tregs)/Th17 imbalance. Methods T cell subpopulations were analyzed by flow cytometry in the peripheral blood of pediatric patients with acute (aBD, n = 24), remitting (rBD, n = 12) BD, and in healthy controls (HC, n = 24). Tregs (CD4+CD25hiCD127-/loFoxp3+), activated Tregs (GITR, LAP, CTLA-4, and HLA-DR expression), CD4+ and CD8+ T cells producing interferon-g (Th1 and Tc1) or interleukin (IL)-17 (Th17 and Tc17) under polyclonal (OKT3/IL-2) or antigenic (Streptococcus sanguis KTH-1 peptides and HSP-60) stimulation, were numerated. Results Th17 (1.9 and 5.1 fold) and Tc17 (4.0 and 2.0 fold) frequency under mitogenic stimulation was significantly increased in aBD and rBD patients as compared with HC. Th17 frequency under antigenic stimulation was also higher in patients than in HC. The percentage and number of Tregs and activated Tregs in patients and in HC were similar. However, when Tregs were removed, antigen-driven differentiation into Th1 and Th17 was significantly boosted in BD but not in HC CD4+T cells. Conclusion There is a bias toward a Th17 polarization in acute and remitting BD children. Although we did not observe an increase in the number of Tregs in these patients, their Tregs limit CD4+T cell differentiation into Th1 and Th17 cells. Thus, in pediatric BD, Tregs seem to incompletely counterbalance a Th17 orientation of the helper T cell response.

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