scholarly journals Impact of Graft-Resident Leucocytes on Treg Mediated Skin Graft Survival

2021 ◽  
Vol 12 ◽  
Author(s):  
Romy Steiner ◽  
Anna M. Weijler ◽  
Thomas Wekerle ◽  
Jonathan Sprent ◽  
Nina Pilat
Keyword(s):  
T Cells ◽  
Graft Survival ◽  
T Cell Activation ◽  
Skin Graft ◽  
Cell Activation ◽  
T Regulatory Cells ◽  
Minor Importance ◽  
Short Term Treatment ◽  
Mhc Molecules ◽  
Significant Prolongation

The importance and exact role of graft-resident leucocytes (also referred to as passenger leucocytes) in transplantation is controversial as these cells have been reported to either initiate or retard graft rejection. T cell activation to allografts is mediated via recognition of intact or processed donor MHC molecules on antigen-presenting cells (APC) as well as through interaction with donor-derived extracellular vesicles. Reduction of graft-resident leucocytes before transplantation is a well-known approach for prolonging organ survival without interfering with the recipient’s immune system. As previously shown by our group, injecting mice with IL-2/anti-IL-2 complexes (IL-2cplx) to augment expansion of CD4 T regulatory cells (Tregs) induces tolerance towards islet allografts, and also to skin allografts when IL-2cplx treatment is supplemented with rapamycin and a short-term treatment of anti-IL-6. In this study, we investigated the mechanisms by which graft-resident leucocytes impact graft survival by studying the combined effects of IL-2cplx-mediated Treg expansion and passenger leucocyte depletion. For the latter, effective depletion of APC and T cells within the graft was induced by prior total body irradiation (TBI) of the graft donor. Surprisingly, substantial depletion of donor-derived leucocytes by TBI did not prolong graft survival in naïve mice, although it did result in augmented recipient leucocyte graft infiltration, presumably through irradiation-induced nonspecific inflammation. Notably, treatment with the IL-2cplx protocol prevented early inflammation of irradiated grafts, which correlated with an influx of Tregs into the grafts. This finding suggested there might be a synergistic effect of Treg expansion and graft-resident leucocyte depletion. In support of this idea, significant prolongation of skin graft survival was achieved if we combined graft-resident leucocyte depletion with the IL-2cplx protocol; this finding correlated along with a progressive shift in the composition of T cells subsets in the grafts towards a more tolerogenic environment. Donor-specific humoral responses remained unchanged, indicating minor importance of graft-resident leucocytes in anti-donor antibody development. These results demonstrate the importance of donor-derived leucocytes as well as Tregs in allograft survival, which might give rise to new clinical approaches.

scholarly journals MHCII glycosylation modulates Bacteroides fragilis carbohydrate antigen presentation

2011 ◽  
Vol 208 (5) ◽  
pp. 1041-1053 ◽  
Author(s):  
Sean O. Ryan ◽  
Jason A. Bonomo ◽  
Fan Zhao ◽  
Brian A. Cobb
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Bacteroides Fragilis ◽  
Carbohydrate Antigen ◽  
Activated T Cells ◽  
Mhc Molecules

N-linked glycans are thought to protect class II major histocompatibility complex (MHC) molecules (MHCII) from proteolytic cleavage and assist in arranging proteins within the immune synapse, but were not thought to directly participate in antigen presentation. Here, we report that antigen-presenting cells (APCs) lacking native complex N-glycans showed reduced MHCII binding and presentation of the T cell activating glycoantigen (GlyAg) polysaccharide A from Bacteroides fragilis but not conventional peptides. APCs lacking native N-glycans also failed to mediate GlyAg-driven T cell activation but activated T cells normally with protein antigen. Mice treated with the mannosidase inhibitor kifunensine to prevent the formation of complex N-glycans were unable to expand GlyAg-specific T cells in vivo upon immunization, yet adoptive transfer of normally glycosylated APCs into these animals overcame this defect. Our findings reveal that MHCII N-glycosylation directly impacts binding and presentation of at least one class of T cell–dependent antigen.

scholarly journals The CD43 130-kD peripheral T-cell activation antigen is downregulated in thymic positive selection

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1725-1732 ◽  
Author(s):  
LG Ellies ◽  
W Tao ◽  
W Fellinger ◽  
HS Teh ◽  
HJ Ziltener
Keyword(s):  
T Cells ◽  
T Cell ◽  
Positive Selection ◽  
T Cell Activation ◽  
Cell Activation ◽  
Class Ii ◽  
Class I ◽  
Double Positive ◽  
Mhc Molecules ◽  
Activation Antigen

Abstract Specific glycoforms of CD43, the major O-glycosylated cell-surface protein on T lymphocytes, can affect cell adhesion according to the types of carbohydrate side chains carried. In the peripheral immune system, CD43 130 kD, which carries core 2 O-glycan structures on its surface, is an activation antigen expressed on both CD4 and CD8 single- positive (SP) T cells. We have previously shown that the 115-kD resting and 130-kD activation glycoforms of murine CD43 are differentially regulated on peripheral SP T cells. In this study, we used transgenic mice expressing T-cell receptors (TCRs) specific for antigens presented by class I and class II major histocompatibility complex (MHC) molecules to determine whether CD43 glycoforms are involved in thymocyte differentiation. Positive selection in these mice results in an increase in the production of CD8 and CD4 SP T cells, respectively, which express the transgenic TCR. Positive selection is also accompanied by the upregulation of TCR, CD69, and CD5. Using these markers to define stages of thymocyte maturation, we found that CD43 130 kD was downregulated in the positive selection of CD4 CD8 double- positive thymocytes expressing a class I but not class II MHC- restricted TCR. These data suggest that core 2 glycosyltransferase (C2GnT) modulated expression of CD43 glycoforms may be involved in thymic selection events.

scholarly journals The CD43 130-kD peripheral T-cell activation antigen is downregulated in thymic positive selection

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1725-1732 ◽  
Author(s):  
LG Ellies ◽  
W Tao ◽  
W Fellinger ◽  
HS Teh ◽  
HJ Ziltener
Keyword(s):  
T Cells ◽  
T Cell ◽  
Positive Selection ◽  
T Cell Activation ◽  
Cell Activation ◽  
Class Ii ◽  
Class I ◽  
Double Positive ◽  
Mhc Molecules ◽  
Activation Antigen

Specific glycoforms of CD43, the major O-glycosylated cell-surface protein on T lymphocytes, can affect cell adhesion according to the types of carbohydrate side chains carried. In the peripheral immune system, CD43 130 kD, which carries core 2 O-glycan structures on its surface, is an activation antigen expressed on both CD4 and CD8 single- positive (SP) T cells. We have previously shown that the 115-kD resting and 130-kD activation glycoforms of murine CD43 are differentially regulated on peripheral SP T cells. In this study, we used transgenic mice expressing T-cell receptors (TCRs) specific for antigens presented by class I and class II major histocompatibility complex (MHC) molecules to determine whether CD43 glycoforms are involved in thymocyte differentiation. Positive selection in these mice results in an increase in the production of CD8 and CD4 SP T cells, respectively, which express the transgenic TCR. Positive selection is also accompanied by the upregulation of TCR, CD69, and CD5. Using these markers to define stages of thymocyte maturation, we found that CD43 130 kD was downregulated in the positive selection of CD4 CD8 double- positive thymocytes expressing a class I but not class II MHC- restricted TCR. These data suggest that core 2 glycosyltransferase (C2GnT) modulated expression of CD43 glycoforms may be involved in thymic selection events.

Selective blockade of CD28 and not CTLA-4 with a single-chain Fv–α1-antitrypsin fusion antibody

Blood ◽  
2003 ◽  
Vol 102 (2) ◽  
pp. 564-570 ◽  
Author(s):  
Bernard Vanhove ◽  
Geneviève Laflamme ◽  
Flora Coulon ◽  
Marie Mougin ◽  
Patricia Vusio ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antibody Fragment ◽  
Single Chain ◽  
Selective Blockade ◽  
Mhc Molecules ◽  
Single Chain Fv

Abstract B7-1 and B7-2 are costimulatory molecules expressed on antigen-presenting cells. The CD28/B7 costimulation pathway is critical for T-cell activation, proliferation, and Th polarization. Blocking both cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and CD28 interactions with a CTLA-4/Ig fusion protein inhibits various immune-mediated processes in vivo, such as allograft rejection and autoimmunity. However, selective blockade of CD28 may represent a better strategy for immunosuppression than B7 blockade, because CTLA-4/B7 interactions have been shown to participate in the extinction of the T-cell receptor–mediated activation signal and to be required for the induction of immunologic tolerance. In addition, selective CD28 inhibition specifically decreases the activation of alloreactive and autoreactive T cells, but not the activation of T cells stimulated by exogenous antigens presented in the context of self major histocompatibility complex (MHC) molecules. CD28 blockade cannot be obtained with anti-CD28 dimeric antibodies, which cluster their target and promote T-cell costimulation, whereas monovalent Fab fragments can block CD28 and reduce alloreactivity. In this study, we report the construction of a monovalent single-chain Fv antibody fragment from a high-affinity antihuman CD28 antibody (CD28.3) that blocked adhesion of T cells to cells expressing the CD28 receptor CD80. Genetic fusion with the long-lived serum protein α1-antitrypsin led to an extended half-life without altering its binding characteristics. The anti-CD28 fusion molecule showed biologic activity as an immuno-suppressant by inhibiting T-cell activation and proliferation in a mixed lymphocyte reaction.

The Early Induction of PDL1 On Monocytes by Ivig Suppresses T Cell Activation in Allogeneic Mixed Lymphocyte Reactions

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4111-4111
Author(s):  
Lauriane Padet ◽  
Renée Bazin
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Survival ◽  
T Cell Activation ◽  
Allograft Rejection ◽  
Cell Activation ◽  
Strong Increase ◽  
Inflammatory Monocyte ◽  
Hla Dr ◽  
Anti Inflammatory

Abstract Abstract 4111 Background: Recognition of histocompatibility determinants by allogeneic T cells together with the engagement of co-stimulatory molecules with their ligands expressed on accessory cells (B7:CD28, CD40:CD40L) is essential for the induction of T cell-mediated allograft rejection. In contrast, the PD1:PDL1 negative co-stimulatory pathway plays a critical role in the induction and maintenance of peripheral transplantation tolerance. Despite the use of potent immunosuppressive therapy for the blockade of co-stimulatory pathways, allograft rejection and drug toxicity remain an important problem in transplanted patients. IVIg was first used as a prophylactic agent in these immunocompromised patients to prevent infections, but several studies have suggested that IVIg also improved the rate of graft survival in patients with high risk for rejection. The mechanisms responsible for this anti-inflammatory effect are unclear and remain to be determined. We recently showed, using the allogeneic mixed lymphocyte reaction (MLR) as an in vitro model of allograft rejection and GvHD, that IVIg strongly inhibited T cell activation. In the present study, we sought to determine the mechanisms underlying this inhibition. Methods: For allogeneic MLR, human peripheral blood mononuclear cells (PBMC) from 2 different individuals were mixed together with or without 2 mg/ml of IVIg and incubated for 4 days prior to determination of IL-2 secretion by ELISA as a measure of T cell activation. The expression of TCR, CD3, CD28 and PD1 on T cells and HLA-DR, CD80, CD86 and PDL1 on monocytes was evaluated by flow cytometry. Results: IVIg strongly inhibited IL-2 secretion (>90%; P<0.001) as previously reported. To explain the inhibition of T cell activation in the presence of IVIg, we postulated that the expression of molecules involved in antigen presentation and in different co-stimulatory pathways was modulated by IVIg. We thus evaluated the effect of IVIg on the cell surface expression of various molecules implicated in T cell activation or tolerance, 24 hours after the onset of the MLR. Our results showed no modulation of TCR, CD3, CD28 and PD1 expression on T cells. Similarly, IVIg did not affect the expression of CD86 on monocytes. In contrast, the expression of CD80 was significantly decreased (>30%; P<0.01) on these cells after IVIg treatment. In addition, a strong increase in PDL1 expression (>70%; P<0.05) on monocytes was observed in MLRs done in the presence of IVIg. Finally, the expression of HLA-DR was increased by >60% (P<0.01) and that of CD14 was decreased by >50% (P<0.01) in the presence of IVIg, which is characteristic of the emergence of an anti-inflammatory monocyte population. Conclusion: Altogether, our results suggest that IVIg induces its immunosuppressive effects in allogeneic MLRs by modulating the expression of co-stimulatory molecules on monocytes and by inducing an anti-inflammatory monocyte population. This study contributes to a better understanding of the mechanisms by which IVIg may induce peripheral tolerance and improve graft survival in transplanted patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals TCR Recognition of Peptide–MHC-I: Rule Makers and Breakers

2020 ◽  
Vol 22 (1) ◽  
pp. 68
Author(s):  
Christopher Szeto ◽  
Christian A. Lobos ◽  
Andrea T. Nguyen ◽  
Stephanie Gras
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Adaptive Immune System ◽  
Human Leukocyte ◽  
Activated T Cells ◽  
Mhc I ◽  
Mhc Molecules

T cells are a critical part of the adaptive immune system that are able to distinguish between healthy and unhealthy cells. Upon recognition of protein fragments (peptides), activated T cells will contribute to the immune response and help clear infection. The major histocompatibility complex (MHC) molecules, or human leukocyte antigens (HLA) in humans, bind these peptides to present them to T cells that recognise them with their surface T cell receptors (TCR). This recognition event is the first step that leads to T cell activation, and in turn can dictate disease outcomes. The visualisation of TCR interaction with pMHC using structural biology has been crucial in understanding this key event, unravelling the parameters that drive this interaction and their impact on the immune response. The last five years has been the most productive within the field, wherein half of current unique TCR–pMHC-I structures to date were determined within this time. Here, we review the new insights learned from these recent TCR–pMHC-I structures and their impact on T cell activation.

scholarly journals Trained Immunity Induced by in Vivo Peptide-Based STAT6 Inhibition Prevents Ragweed Allergy in Mice

2020 ◽  
Author(s):  
Husheem Michael ◽  
Yuanyi Li ◽  
Yufa Wang ◽  
Christine T. McCusker
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Regulatory Cells ◽  
Pulmonary Inflammation ◽  
Specific Ige ◽  
Gene Expressions ◽  
Inhibitory Peptide ◽  
Sensitization Phase

Abstract BackgroundAllergic airways disease (AAD) is initiated, maintained by the type 2 (T2) inflammatory pathway, and is partially regulated by cytokines IL-4 and IL-13 following activation of the STAT6 transcription factor. ObjectiveTo investigate mucosal immune responses, using neonatal vaccination with the STAT6 inhibitory peptide (STAT6-IP), to prevent the development of ragweed-induced AAD. MethodsWe demonstrate that transfer of CD4+ T cells or dendritic cells (DC) from STAT6-IP vaccinated wild-type BALB/c mice to naïve mice, that were subsequently chronically exposed to sensitizing doses of ragweed allergen, is sufficient to prevent development of T2 responses in recipients. ResultsOur results demonstrate significant reductions in; airways hyperresponsiveness (AHR); ragweed-specific IgE; pulmonary inflammation; T2 cytokines; and inflammatory gene expressions in recipient mice. Expression of IDO, TGFβ and T regulatory cells were all significantly increased. Anti-TGFβ treatment during the ragweed sensitization phase re-constituted the pro-inflammatory T2 immune response. We show that tolerance can be attained via DC or T cells trained in the STAT6-IP-mediated tolerant milieu. This effect is not restricted to a particular allergen and does not require antigen-mediated T cell activation prior to transfer. ConclusionThese data indicate that early transient STAT6-inhibition constitutes an effective immunomodulatory airways allergy preventative strategy.

scholarly journals Probiotic supplementation reduces inflammatory profiles but does not prevent oral immune perturbations during SIV infection

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rhianna Jones ◽  
Kyle Kroll ◽  
Courtney Broedlow ◽  
Luca Schifanella ◽  
Scott Smith ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Rhesus Macaques ◽  
Oral Microbiome ◽  
Probiotic Supplementation ◽  
Siv Infection ◽  
Anti Inflammatory

AbstractHIV/SIV infections lead to massive loss of mucosal CD4 + T cells and breakdown of the epithelial mucosa resulting in severe microbial dysbiosis and chronic immune activation that ultimately drive disease progression. Moreover, disruption of one of the most understudied mucosal environments, the oral cavity, during HIV-induced immunosuppression results in significant microbial and neoplastic co-morbidities and contributes to and predicts distal disease complications. In this study we evaluated the effects of oral probiotic supplementation (PBX), which can stimulate and augment inflammatory or anti-inflammatory pathways, on early SIV infection of rhesus macaques. Our study revealed that similar to the GI mucosae, oral CD4 + T cells were rapidly depleted, and as one of the first comprehensive analyses of the oral microflora in SIV infection, we also observed significant modulation among two genera, Porphyromonas and Actinobacillus, early after infection. Interestingly, although PBX therapy did not substantially protect against oral dysbiosis or ameliorate cell loss, it did somewhat dampen inflammation and T cell activation. Collectively, these data provide one of the most comprehensive evaluations of SIV-induced changes in oral microbiome and CD4 + T cell populations, and also suggest that oral PBX may have some anti-inflammatory properties in lentivirus infections.

scholarly journals Controlling T cells spreading, mechanics and activation by micropatterning

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anaïs Sadoun ◽  
Martine Biarnes-Pelicot ◽  
Laura Ghesquiere-Dierickx ◽  
Ambroise Wu ◽  
Olivier Théodoly ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Young Modulus ◽  
Careful Examination ◽  
Adhesion Receptor ◽  
Force Microscopy ◽  
Atomic Force ◽  
Micro Patterns

AbstractWe designed a strategy, based on a careful examination of the activation capabilities of proteins and antibodies used as substrates for adhering T cells, coupled to protein microstamping to control at the same time the position, shape, spreading, mechanics and activation state of T cells. Once adhered on patterns, we examined the capacities of T cells to be activated with soluble anti CD3, in comparison to T cells adhered to a continuously decorated substrate with the same density of ligands. We show that, in our hand, adhering onto an anti CD45 antibody decorated surface was not affecting T cell calcium fluxes, even adhered on variable size micro-patterns. Aside, we analyzed the T cell mechanics, when spread on pattern or not, using Atomic Force Microscopy indentation. By expressing MEGF10 as a non immune adhesion receptor in T cells we measured the very same spreading area on PLL substrates and Young modulus than non modified cells, immobilized on anti CD45 antibodies, while retaining similar activation capabilities using soluble anti CD3 antibodies or through model APC contacts. We propose that our system is a way to test activation or anergy of T cells with defined adhesion and mechanical characteristics, and may allow to dissect fine details of these mechanisms since it allows to observe homogenized populations in standardized T cell activation assays.

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