scholarly journals A252 FUNCTIONAL ANALYSIS OF GENETIC AETIOLOGIES IN A DOWNSTREAM OF TYROSINE KINASE (DOK) PROTEIN IN THE PATHOGENESIS OF PEDIATRIC INFLAMMATORY BOWEL DISEASE (IBD)

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. 129-130
Author(s):  
V Batura ◽  
C Guo ◽  
N Warner ◽  
G Leung ◽  
A Ricciuto ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Imaging Techniques ◽  
Inflammatory Disorder ◽  
Zebrafish Model ◽  
Peripheral Blood Mononuclear

Abstract Background IBD is a form of chronic inflammatory disorder of the gastrointestinal tract that arises due to genetic, environmental, immunological and microbial factors. The precise pathological mechanisms remain elusive. It is thought that the onset of pediatric IBD can largely be attributed to genetics. Muise lab, at SickKids, regularly screens children at the SickKids IBD clinic and through an international consortium to find possible genetic links to the disease. We report a patient at SickKids with biallelic mutations in DOK4 who has severe Crohn’s Disease along with other inflammatory conditions. Downstream of kinase (DOK) proteins are a family of adaptor molecules that serve as scaffolding proteins important in regulating cell signaling, especially in T cells. DOK4 has been shown to have negative regulatory effects on T cell activation but is also expressed across various other tissues where its function is yet to be determined. We predict that these mutations are causing immune cell dysregulation, which may be contributing to the patients IBD. Aims Through this study, we aim to enhance our understanding of the pathobiological mechanism of novel mutations in DOK4. Methods We have established T cell lines, expressing wild type and mutated DOK4, which will be used to perform functional tests, such as localization analysis through immunofluorescence and cytokine profiling, to check for T cell function. We have patient derived organoids, which will be used to assess changes in gut morphology using imaging techniques. We will also generate mutant zebrafish model that will be used to determine the susceptibility to colitis related to this mutation, disease progression and gut peristalsis using live imaging technology. Results Preliminary data shows variation in expression of the protein within patient derived peripheral blood mononuclear cells (PBMCs) compared to a healthy donor. Conclusions With this study, we hope to identify new therapeutic targets for patients with DOK4 mutations. Funding Agencies CIHRThe Leona M. and Harry B. Helmsley Charitable Trust

scholarly journals Endogenous retrovirus-encoded Syncytin-2 contributes to exosome-mediated immunosuppression of T cells†

2019 ◽  
Author(s):  
Adjimon G Lokossou ◽  
Caroline Toudic ◽  
Phuong Trang Nguyen ◽  
Xavier Elisseeff ◽  
Amandine Vargas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Map Kinases ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Endogenous Retrovirus ◽  
Jurkat Cells ◽  
Peripheral Blood Mononuclear ◽  
Interfering Rna

Abstract Modulation of the activation status of immune cell populations during pregnancy depends on placental villous cytotrophoblast (VCT) cells and the syncytiotrophoblast (STB). Failure in the establishment of this immunoregulatory function leads to pregnancy complications. Our laboratory has been studying Syncytin-2 (Syn-2), an endogenous retroviral protein expressed in placenta and on the surface of placental exosomes. This protein plays an important role not only in STB formation through its fusogenic properties, but also through its immunosuppressive domain (ISD). Considering that Syn-2 expression is importantly reduced in preeclamptic placentas, we were interested in addressing its possible immunoregulatory effects on T cells. Activated Jurkat T cells and peripheral blood mononuclear cells (PBMCs) were treated with monomeric or dimerized version of a control or a Syn-2 ISD peptide. Change in phosphorylation levels of ERK1/2 MAP kinases was selectively noted in Jurkat cells treated with the dimerized ISD peptide. Upon incubation with the dimerized Syn-2 ISD peptide, significant reduction in Th1 cytokine production was further demonstrated by ELISA and Human Th1/Th2 Panel Multi-Analyte Flow Assay. To determine if exosome-associated Syn-2 could also be immunosuppressive placental exosomes were incubated with activated Jurkat and PBMCs. Quantification of Th1 cytokines in the supernatants revealed severe reduction in T cell activation. Interestingly, exosomes from Syn-2-silenced VCT incubated with PBMCs were less suppressive when compared with exosome derived from VCT transfected with control small interfering RNA (siRNA). Our results suggest that Syn-2 is an important immune regulator both locally and systemically, via its association with placental exosomes.

PBMC-07- Stimulation of human peripheral blood mononuclear cells with immobilized anti-CD3 and soluble anti-CD28 antibodies. v1

2021 ◽  
Author(s):  
Alessia Furgiuele ◽  
Massimilano Legnaro ◽  
Alessandra Luini ◽  
Marco Ferrari ◽  
Emanuela Rasini ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Functional Responses ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

This protocol was designed to activate the lymphocytes T of a population of peripheral blood mononuclear cells (PBMCs), simulating their physiological response to antigen/MHC complex acting on T Cell Receptors-TCR , in order to test their functional responses including cell proliferation and cytokine production. The co-stimulation protocol include: i)anti-CD3 antibody a polyclonal activator specific for invariant framework epitopes on TCR complex (in particular, we use UCHT1 clone an anti-human CD3 antibody that recognizes the ε-chain of CD3 which is used for immobilized option of activation) (http://static.bdbiosciences.com/documents/BD_Tcell_Human_CD3_Activation_Protocol.pdf) ii) anti-CD28 antibody used to cooperate with TCR signals promoting activation of T cells The procedure has been reproduced following the indications contained in the protocol of "EBiooscience" (https://tools.thermofisher.com/content/sfs/manuals/t-cell-activation-in-vitro.pdf). Pilot experiments on PBMC were carried out to determine the best concentrations of anti-CD3 and anti-CD28 to induce optimal proliferation of PBMC and production of cytokines TNF-α and IFN-γ. We found a dose dependent correlation between immobilized anti-CD3 and cells functional responses. The selected amount was 2 µg/mL for both anti-CD3 and anti-CD28 that was the concentration below the maximum response which allows also to test possible modulations by therapeutic agents. References http://static.bdbiosciences.com/documents/BD_Tcell_Human_CD3_Activation_Protocol.pdf https://tools.thermofisher.com/content/sfs/manuals/t-cell-activation-in-vitro.pdf https://www.bdbiosciences.com/ds/pm/tds/555330.pdf https://www.bdbiosciences.com/ds/pm/tds/555726.pdf BEFORE STARTING with this procedure Moreover, work under laminar flow hood when you are processing samples from the beginning to the end of the culture. Make sure you are using,sterile culture mediumand sterile plastic disposable as well.

scholarly journals DNAM1 and TIGIT balance the T cell response, with low T cell TIGIT expression corresponding to inflammation in psoriatic disease

2020 ◽  
Author(s):  
M E Jacobs ◽  
J N Pouw ◽  
M A Olde Nordkamp ◽  
T R D J Radstake ◽  
E F A Leijten ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Inverse Correlation ◽  
T Cell Response ◽  
Peripheral Blood Mononuclear ◽  
Psoriatic Disease

Abstract Background Signals at the contact site of antigen-presenting cells (APCs) and T cells help orchestrate the adaptive immune response. CD155 on APCs can interact with the stimulatory receptor DNAM1 or inhibitory receptor TIGIT on T cells. The CD155/DNAM1/TIGIT axis is under extensive investigation as immunotherapy target in inflammatory diseases including cancer, chronic infection and autoimmune diseases. We investigated a possible role for CD155/DNAM1/TIGIT signaling in psoriatic disease. Methods By flow cytometry we analyzed peripheral blood mononuclear cells of patients with psoriasis (n=20) or psoriatic arthritis (n=21), and healthy individuals (n=7). We measured CD155, TIGIT and DNAM1 expression on leukocyte subsets and compared activation-induced cytokine production between CD155-positive and -negative APCs. We assessed the effects of TIGIT and DNAM1 blockade on T cell activation, and related the expression of CD155/DNAM1/TIGIT axis molecules to measures of disease activity. Results High CD155 expression associates with TNF production in myeloid and plasmacytoid dendritic cells (DC). In CD1c+ myeloid DC, activation-induced CD155 expression associates with increased HLA-DR expression. CD8 T cells - but not CD4 T cells - express high levels of TIGIT. DNAM1 blockade decreases T cell pro-inflammatory cytokine production, while TIGIT blockade increased T cell proliferation. Finally, T cell TIGIT expression shows an inverse correlation with inflammation biomarkers in psoriatic disease. Conclusion CD155 is increased on pro-inflammatory APCs, while the receptors DNAM1 and TIGIT expressed on T cells balance the inflammatory response by T cells. In psoriatic disease, low TIGIT expression on T cells is associated with systemic inflammation.

scholarly journals IMMU-46. EXAMINATION OF THE EFFECTS OF DEXAMETHASONE ON THE EFFICACY OF IMMUNOTHERAPY IN GLIOMA USING GENE-MEDIATED CYTOTOXIC IMMUNOTHERAPY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi129-vi129
Author(s):  
Marilin Koch ◽  
Mykola Zdioruk ◽  
M Oskar Nowicki ◽  
Estuardo Aguilar ◽  
Laura Aguilar ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Symptomatic Treatment ◽  
Tumor Cell Death ◽  
The Impact

Abstract RATIONALE Dexamethasone is frequently used in symptomatic treatment of glioma patients, although it is known to cause immune suppression. Checkpoint inhibitor immunotherapies have not yet been successful in glioma treatments. Gene-mediated cytotoxic immunotherapy (GMCI) is an immunotherapeutic approach that uses aglatimagene besadenovec with an anti-herpetic prodrug to induce immunogenic tumor cell death and immune cell attraction to the tumor site with potent CD8 T cell activation. GMCI is currently in clinical trials for solid tumors including glioblastoma, where it showed encouraging survival results in a Phase 2 study that did not limit the use of dexamethasone. However, the effects of dexamethasone on its efficacy have not been explored. METHODS We investigated the effects of dexamethasone on GMCI in vitro using cytotoxicity and T-cell-killing assays in glioblastoma cell lines. The impact of dexamethasone in vivo was assessed in an orthotopic syngeneic murine glioblastoma model. RESULTS Cyotoxicity assays showed that Dexamethasone has a slight impact on GMCI in vitro. In contrast, we observed a highly significant effect in T-cell-functional assays in which killing was greatly impaired. Immune cell response assays revealed a reduced T-cell proliferation after co-culture with supernatant from dexamethasone or combination treated glioblastoma cells in contrast to GMCI alone. In a murine model, the combination of GMCI and dexamethasone resulted in a significant reduction in median symptom-free survival (29d) in comparison to GMCI alone (39.5d) (P = 0.0184). CONCLUSION Our data suggest that high doses of dexamethasone may negatively impact the efficacy of immunotherapy for glioma, which may be a consequence of impaired T cell function. These results support the idea that there is a need in identifying possible alternatives to dexamethasone to maximize the effectiveness of immunostimulatory therapies such as GMCI.

scholarly journals GABAA receptor α4-subunit knockout enhances lung inflammation and airway reactivity in a murine asthma model

2017 ◽  
Vol 313 (2) ◽  
pp. L406-L415 ◽  
Author(s):  
Gene T. Yocum ◽  
Damian L. Turner ◽  
Jennifer Danielsson ◽  
Matthew B. Barajas ◽  
Yi Zhang ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Immune Cells ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Asthma Model

Emerging evidence indicates that hypnotic anesthetics affect immune function. Many anesthetics potentiate γ-aminobutyric acid A receptor (GABAAR) activation, and these receptors are expressed on multiple subtypes of immune cells, providing a potential mechanistic link. Like immune cells, airway smooth muscle (ASM) cells also express GABAARs, particularly isoforms containing α4-subunits, and activation of these receptors leads to ASM relaxation. We sought to determine if GABAAR signaling modulates the ASM contractile and inflammatory phenotype of a murine allergic asthma model utilizing GABAAR α4-subunit global knockout (KO; Gabra40/0) mice. Wild-type (WT) and Gabra4 KO mice were sensitized with house dust mite (HDM) antigen or exposed to PBS intranasally 5 days/wk for 3 wk. Ex vivo tracheal rings from HDM-sensitized WT and Gabra4 KO mice exhibited similar magnitudes of acetylcholine-induced contractile force and isoproterenol-induced relaxation ( P = not significant; n = 4). In contrast, in vivo airway resistance (flexiVent) was significantly increased in Gabra4 KO mice ( P < 0.05, n = 8). Moreover, the Gabra4 KO mice demonstrated increased eosinophilic lung infiltration ( P < 0.05; n = 4) and increased markers of lung T-cell activation/memory (CD62L low, CD44 high; P < 0.01, n = 4). In vitro, Gabra4 KO CD4+ cells produced increased cytokines and exhibited increased proliferation after stimulation of the T-cell receptor as compared with WT CD4+ cells. These data suggest that the GABAAR α4-subunit plays a role in immune cell function during allergic lung sensitization. Thus GABAAR α4-subunit-specific agonists have the therapeutic potential to treat asthma via two mechanisms: direct ASM relaxation and inhibition of airway inflammation.

scholarly journals Characterization of the T-Cell Receptor Vβ Repertoire in the Human Immune Response against Leishmania Parasites

2006 ◽  
Vol 74 (8) ◽  
pp. 4757-4765 ◽  
Author(s):  
Jorge Clarêncio ◽  
Camila I. de Oliveira ◽  
Glória Bomfim ◽  
Margarida M. Pompeu ◽  
Maria Jania Teixeira ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Cell Receptor ◽  
Peripheral Blood Mononuclear ◽  
Cell Clones ◽  
Human Immune Response ◽  
Lymph Node Cells

ABSTRACT In order to explore a possible presence of hyperreactive T-cell clones in human cutaneous leishmaniasis (CL), we have investigated, by flow cytometry, the expression of Vβ chains of T-cell receptors (TCRs) in the following types of cells: (i) peripheral blood mononuclear cells (PBMCs) from CL patients, which were then compared to those from normal volunteers; (ii) unstimulated and soluble Leishmania antigen-stimulated draining lymph node cells from CL patients; (iii) PBMCs from volunteers before versus after Leishmania immunization; and (iv) PBMCs from healthy volunteers that were primed in vitro with live Leishmania parasites. Our results show a modulation in the TCR Vβ repertoire during CL and after antigen stimulation of patients' cells. Vaccination, however, leads to a broad expansion of different Vβ TCRs. We also observed an association between TCR Vβ12 expression, T-cell activation, and gamma interferon production upon in vitro priming with Leishmania. Collectively, these results both indicate that infection with live parasites or exposure to parasite antigen can modulate the TCR Vβ repertoire and suggest that TCR Vβ12 may be implicated in the response to Leishmania.

scholarly journals Differential effects of IL-21 and IL-15 on perforin expression, lysosomal degranulation, and proliferation in CD8 T cells of patients with human immunodeficiency virus-1 (HIV)

Blood ◽  
2006 ◽  
Vol 109 (9) ◽  
pp. 3873-3880 ◽  
Author(s):  
Lesley White ◽  
Subramaniam Krishnan ◽  
Natasa Strbo ◽  
Huanliang Liu ◽  
Michael A. Kolber ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Highly Active Antiretroviral Therapy ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Cell Receptor ◽  
Peripheral Blood Mononuclear ◽  
Perforin Expression

Abstract An urgent need exists to devise strategies to augment antiviral immune responses in patients with HIV who are virologically well controlled and immunologically stable on highly active antiretroviral therapy (HAART). The objective of this study was to compare the immunomodulatory effects of the cytokines interleukin (IL)–21 with IL-15 on CD8 T cells in patients with HIV RNA of less than 50 copies/mL and CD4 counts greater than 200 cells/mm.3 Patient CD8 T cells displayed skewed maturation and decreased perforin expression compared with healthy controls. Culture of freshly isolated patient peripheral-blood mononuclear cells (PBMCs) for 5 hours to 5 days with IL-21 resulted in up-regulation of perforin in CD8 T cells, including memory and effector subsets and virus-specific T cells. IL-21 did not induce T-cell activation or proliferation, nor did it augment T-cell receptor (TCR)–induced degranulation. Treatment of patient PBMCs with IL-15 resulted in induction of perforin in association with lymphocyte proliferation and augmentation of TCR-induced degranulation. Patient CD8 T cells were more responsive to cytokine effects than the cells of healthy volunteers. We conclude that CD8 T cells of patients with HIV can be modulated by IL-21 to increase perforin expression without undergoing overt cellular activation. IL-21 could potentially be useful for its perforin-enhancing properties in anti-HIV immunotherapy.

scholarly journals Nanoengineering of Immune Cell Function

2009 ◽  
Vol 1209 ◽  
Author(s):  
Keyue Shen ◽  
Michael C Milone ◽  
Michael L. Dustin ◽  
Lance Cameron Kam
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Cell Communication ◽  
Cell Therapies ◽  
Nano Scale

AbstractT lymphocytes are a key regulatory component of the adaptive immune system. Understanding how the micro- and nano-scale details of the extracellular environment influence T cell activation may have wide impact on the use of T cells for therapeutic purposes. In this article, we examine how the micro- and nano-scale presentation of ligands to cell surface receptors, including microscale organization and nanoscale mobility, influences the activation of T cells. We extend these studies to include the role of cell-generated forces, and the rigidity of the microenvironment, on T cell activation. These approaches enable delivery of defined signals to T cells, a step toward understanding the cell-cell communication in the immune system, and developing micro/nano- and material- engineered systems for tailoring immune responses for adoptive T cell therapies.

scholarly journals Decreased Expression of the CD3ζ Chain in T Cells Infiltrating the Synovial Membrane of Patients with Osteoarthritis

2004 ◽  
Vol 11 (1) ◽  
pp. 195-202 ◽  
Author(s):  
Lazaros I. Sakkas ◽  
George Koussidis ◽  
Efthimios Avgerinos ◽  
John Gaughan ◽  
Chris D. Platsoucas
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Activated T Cells ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
T Cell Stimulation ◽  
Inflammatory Infiltrates

ABSTRACT Osteoarthritis (OA) is a heterogeneous disease which rheumatologists consider to be noninflammatory. However, recent studies suggest that, at least in certain patients, OA is an inflammatory disease and that patients often exhibit inflammatory infiltrates in the synovial membranes (SMs) of macrophages and activated T cells expressing proinflammatory cytokines. We report here that the expression of CD3ζ is significantly decreased in T cells infiltrating the SMs of patients with OA. The CD3ζ chain is involved in the T-cell signal transduction cascade, which is initiated by the engagement of the T-cell antigen receptor and which culminates in T-cell activation. Double immunofluorescence of single-cell suspensions derived from the SMs from nine patients with OA revealed significantly increased proportions of CD3ε-positive (CD3ε+) cells compared with the proportions of CD3ζ-positive (CD3ζ+) T cells (means ± standard errors of the means, 80.48% ± 3.92% and 69.02% ± 6.51%, respectively; P = 0.0096), whereas there were no differences in the proportions of these cells in peripheral blood mononuclear cells (PBMCs) from healthy donors (94.73% ± 1.39% and 93.79% ± 1.08%, respectively; not significant). The CD3ζ+ cell/CD3ε+ cell ratio was also significantly decreased for T cells from the SMs of patients with OA compared with that for T cells from the PBMCs of healthy donors (0.84 ± 0.17 and 0.99 ± 0.01, respectively; P = 0.0302). The proportions of CD3ε+ CD3ζ+ cells were lower in the SMs of patients with OA than in the PBMCs of healthy donors (65.04% ± 6.7% and 90.81% ± 1.99%, respectively; P = 0.0047). Substantial proportions (about 15%) of CD3ε+ CD3ζ-negative (CD3ζ−) and CD3ε-negative (CD3ε−) CD3ζ− cells were found in the SMs of patients with OA. Amplification of the CD3ζ and CD3δ transcripts from the SMs of patients with OA by reverse transcriptase PCR consistently exhibited stronger bands for CD3δ cDNA than for CD3ζ cDNA The CD3ζ/CD3δ transcript ratio in the SMs of patients with OA was significantly lower than that in PBMCs from healthy controls (P < 0.0001). These results were confirmed by competitive MIMIC PCR. Immunoreactivities for the CD3ζ protein were detected in the SMs of 10 of 19 patients with OA, and they were of various intensities, whereas SMs from all patients were CD3ε+ (P = 0.0023). The decreased expression of the CD3ζ transcript and protein in T cells from the SMs of patients with OA relative to that of the CD3ε transcript is suggestive of chronic T-cell stimulation and supports the concept of T-cell involvement in OA.

Stealth Cells: Prevention of Major Histocompatibility Complex Class II-Mediated T-Cell Activation by Cell Surface Modification

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 2135-2141 ◽  
Author(s):  
Kari L. Murad ◽  
Edmund J. Gosselin ◽  
John W. Eaton ◽  
Mark D. Scott
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Flow Cytometric Analysis ◽  
Class Ii ◽  
Immune Recognition ◽  
Dependent Manner ◽  
Peripheral Blood Mononuclear ◽  
Initial Adhesion

Abstract Transfusion or transplantation of T lymphocytes into an allogeneic recipient can evoke potent immune responses including, in immunocompromised patients, graft-versus-host disease (GVHD). As our previous studies demonstrated attenuated immunorecognition of red blood cells covalently modified with methoxy(polyethylene glycol) (mPEG), we hypothesized that T-cell activation by foreign antigens might similarly be prevented by mPEG modification. Mixed lymphocyte reactions (MLR) using peripheral blood mononuclear cells (PBMC) from HLA class II disparate donors demonstrate that mPEG modification of PBMC effectively inhibits T-cell proliferation (measured by 3H-thymidine incorporation) in a dose-dependent manner. Even slight derivatization (0.4 mmol/L mPEG per 4 × 106 cells) resulted in a ≥75% decrease, while higher concentrations caused ≥96% decrease in proliferation. Loss of PBMC proliferation was not due to either mPEG-induced cytotoxicity, as viability was normal, or cellular anergy, as phytohemagglutinin (PHA)-stimulated mPEG-PBMC demonstrated normal proliferative responses. Addition of exogenous interleukin (IL)-2 also had no proliferative effect, suggesting that the mPEG-modified T cells were not antigen primed. Flow cytometric analysis demonstrates that mPEG-modification dramatically decreases antibody recognition of multiple molecules involved in essential cell:cell interactions, including both T-cell molecules (CD2, CD3, CD4, CD8, CD28, CD11a, CD62L) and antigen-presenting cell (APC) molecules (CD80, CD58, CD62L) likely preventing the initial adhesion and costimulatory events necessary for immune recognition and response.

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