scholarly journals MHC structure and function − antigen presentation. Part 2

2015 ◽  
Vol 13 (1) ◽  
pp. 157-162 ◽  
Author(s):  
Anna Carla Goldberg ◽  
Luiz Vicente Rizzo
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Structure And Function ◽  
Alternative Sources ◽  
And Function ◽  
Significant Class

The second part of this review deals with the molecules and processes involved in the processing and presentation of the antigenic fragments to the T-cell receptor. Though the nature of the antigens presented varies, the most significant class of antigens is proteins, processed within the cell to be then recognized in the form of peptides, a mechanism that confers an extraordinary degree of precision to this mode of immune response. The efficiency and accuracy of this system is also the result of the myriad of mechanisms involved in the processing of proteins and production of peptides, in addition to the capture and recycling of alternative sources aiming to generate further diversity in the presentation to T-cells.

scholarly journals 173 Expression of a membrane-tethered IL-15/IL-15 receptor fusion protein enhances the persistence of MSLN-targeted TRuC-T cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A185-A185
Author(s):  
Michelle Fleury ◽  
Derrick McCarthy ◽  
Holly Horton ◽  
Courtney Anderson ◽  
Amy Watt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Fusion Protein ◽  
T Cell Receptor ◽  
Cytokine Production ◽  
Cell Receptor ◽  
Great Promise ◽  
And Function

BackgroundAdoptive cell therapies have shown great promise in hematological malignancies but have yielded little progress in the context of solid tumors. We have developed T cell receptor fusion construct (TRuC®) T cells, which are equipped with an engineered T cell receptor that utilizes the full complement of TCR signaling subunits and recognizes tumor-associated antigens independent of HLA. In clinical trials, mesothelin (MSLN)-targeting TRuC-T cells (TC-210 or gavo-cel) have shown unprecedented results in patients suffering from advanced mesothelioma and ovarian cancer. To potentially increase the depth of response, we evaluated strategies that can promote intra-tumoral T cell persistence and function. Among the common ??-chain cytokines, IL-15 uniquely supports the differentiation and maintenance of memory T cell subsets by limiting terminal differentiation and conferring resistance to IL-2 mediated activation-induced cell death (AICD). In the studies described here, we evaluated the potential of IL-15 as an enhancement to TRuC-T cell phenotype, persistence and function against MSLN+ targets.MethodsPrimary human T cells were activated and transduced with a lentiviral vector encoding an anti-MSLN binder fused to CD3ε alone or co-expressed with a membrane-tethered IL-15rα/IL-15 fusion protein (IL-15fu). Transduced T cells were expanded for 9 days and characterized for expression of the TRuC, IL-15rα and memory phenotype before subjecting them to in vitro functional assays to evaluate cytotoxicity, cytokine production, and persistence. In vivo efficacy was evaluated in MHC class I/II deficient NSG mice bearing human mesothelioma xenografts.ResultsIn vitro, co-expression of the IL-15fu led to similar cytotoxicity and cytokine production as TC-210, but notably enhanced T-cell expansion and persistence upon repeated stimulation with MSLN+ cell lines. Furthermore, the IL-15fu-enhanced TRuC-T cells sustained a significantly higher TCF-1+ population and retained a stem-like phenotype following activation. Moreover, the IL-15fu-enhanced TRuCs demonstrated robust in vivo expansion and intra-tumoral accumulation as measured by ex vivo analysis of TRuC+ cells in the tumor and blood, with a preferential expansion of CD8+ T cells. Finally, IL-15fu-enhanced TRuC-T cells could be observed in the blood long after the tumors were cleared.ConclusionsThese pre-clinical studies suggest that the IL-15fu can synergize with TC-210 to increase the potency and durability of response in patients with MSLN+ tumors.Ethics ApprovalAll animal studies were approved by the respective Institutional Animal Care and Use Committees.

scholarly journals Enhancing and inhibitory motifs have coevolved to regulate CD4 activity

2021 ◽  
Author(s):  
Mark S. Lee ◽  
Peter J. Tuohy ◽  
Caleb Kim ◽  
Katrina Lichauco ◽  
Heather L. Parrish ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Purifying Selection ◽  
Cell Receptor ◽  
Specific Information ◽  
Transmembrane Receptors ◽  
Peptide Antigens ◽  
And Function ◽  
Intracellular Domains

SUMMARYCD4+ T cells use T cell receptor (TCR)-CD3 complexes, and CD4, to respond to peptide antigens within MHCII molecules (pMHCII). We report here that, through ∼435 million years of evolution in jawed vertebrates, purifying selection has shaped motifs in the extracellular, transmembrane, and intracellular domains of eutherian CD4 that both enhance pMHCII responses and are coevolving with residues in an intracellular motif that inhibits pMHCII responses. Importantly, while CD4 interactions with the Src kinase, Lck, are classically viewed as the key determinant of CD4’s contribution to pMHCII responses, we found that without the inhibitory motif CD4-Lck interactions are not necessary for robust responses to pMHCII. In summary, motifs that mediate events on the outside and inside of CD4+ T cells coevolved to finetune the relay of pMHCII-specific information across the membrane. These results have implications for the evolution and function of complex transmembrane receptors and for biomimetic engineering.

scholarly journals Structure and function of a potent agonist for the semi-invariant natural killer T cell receptor

2005 ◽  
Vol 6 (8) ◽  
pp. 810-818 ◽  
Author(s):  
Dirk M Zajonc ◽  
Carlos Cantu ◽  
Jochen Mattner ◽  
Dapeng Zhou ◽  
Paul B Savage ◽  
...  
Keyword(s):  
T Cell ◽  
Natural Killer ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Structure And Function ◽  
Natural Killer T Cell ◽  
Potent Agonist ◽  
And Function ◽  
Invariant Natural Killer ◽  
Killer T Cell

scholarly journals Increased Activation and Oligoclonality of Peripheral CD8+ T Cells in the Chronic Human Helminth Infection Alveolar Echinococcosis

2002 ◽  
Vol 70 (3) ◽  
pp. 1168-1174 ◽  
Author(s):  
Burkhard J. Manfras ◽  
Stefan Reuter ◽  
Thomas Wendland ◽  
Peter Kern
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Alveolar Echinococcosis ◽  
Ex Vivo ◽  
Active Role ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
And Function

ABSTRACT Alveolar echinococcosis (AE) in humans is a chronic disease characterized by slowly expanding liver lesions. Cellular immunity restricts the spreading of the extracellular pathogen, but functional contributions of CD4+ and CD8+ T cells are not defined. Here we studied ex vivo the phenotype and function of circulating T-cell subsets in AE patients by means of flow cytometry, T-cell receptor spectratyping, and lymphocyte proliferation. AE patients with parasitic lesions displayed a significant increase of activation of predominantly CD8+ T cells compared to healthy controls and AE patients without lesions. In vitro, proliferative T-cell responses to polyclonal stimulation with recall antigens and Echinococcus multilocularis vesicular fluid antigen were sustained during chronic persisting infection in all AE patients. Only in AE patients with parasitic lesions did T-cell receptor spectratyping reveal increased oligoclonality of CD8+ but not CD4+ T cells, suggesting a persistent antigenic drive for CD8+ T cells with subsequent proliferation of selected clonotypes. Thus, our data provide strong evidence for an active role of CD8+ T cells in AE.

scholarly journals The T cell receptor repertoire reflects the dynamics of the immune response to vaccination

2021 ◽  
Author(s):  
Kevin Mohammed ◽  
Austin Meadows ◽  
Sandra Hatem ◽  
Viviana Simon ◽  
Anitha D Jayaprakash ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Influenza Vaccine ◽  
T Cell Receptor ◽  
Cell Response ◽  
Cell Receptor ◽  
Physical Symptoms ◽  
T Cell Response ◽  
Tcr Repertoire

Early, high-resolution metrics are needed to ascertain the immune response to vaccinations. The T cell receptor (TCR), a heterodimer of one α and one β chain, is a promising target, with the complete TCR repertoire reflecting the T cells present in an individual. To this end, we developed Tseek, an unbiased and accurate method for profiling the TCR repertoire by sequencing the TCR α and β chains and developing a suite of tools for repertoire analysis. An added advantage is the ability to non-invasively analyze T cells in peripheral blood mononuclear cells (PBMCs). Tseek and the analytical suite were used to explore the T cell response to both the COVID-19 mRNA vaccine (n=9) and the seasonal inactivated Influenza vaccine (n=5) at several time points. Neutralizing antibody titers were also measured in the covid vaccine samples. The COVID-19 vaccine elicited a broad T cell response involving multiple expanded clones, whereas the Influenza vaccine elicited a narrower response involving fewer clones. Many distinct T cell clones responded at each time point, over a month, providing temporal details lacking in the antibody measurements, especially before the antibodies are detectable. In individuals recovered from a SARS-CoV-2 infection, the first vaccine dose elicited a robust T cell response, while the second dose elicited a comparatively weaker response, indicating a saturation of the response. The physical symptoms experienced by the recipients immediately following the vaccinations were not indicative of the TCR/antibody responses, while a weak TCR response seemed to presage a weak antibody response. We also found that the TCR repertoire acts as an individual fingerprint: donors of blood samples taken years apart could be identified solely based upon their TCR repertoire, hinting at other surprising uses the TCR repertoire may have. These results demonstrate the promise of TCR repertoire sequencing as an early and sensitive measure of the adaptive immune response to vaccination, which can help improve immunogen selection and optimize vaccine dosage and spacing between doses.

scholarly journals Adoptive Transfer of Tracer-Alloreactive CD4+T Cell Receptor Transgenic T Cells Alters the Endogenous Immune Response to an Allograft

2016 ◽  
Vol 16 (10) ◽  
pp. 2842-2853 ◽  
Author(s):  
M. L. Miller ◽  
J. Chen ◽  
M. D. Daniels ◽  
M. G. McKeague ◽  
Y. Wang ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Adoptive Transfer ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
Endogenous Immune Response

The Role of the Zeta Chain in the Expression, Structure and Function of the T Cell Receptor

1989 ◽  
pp. 21-24
Author(s):  
Richard D. Klausner ◽  
Allan M. Weissman ◽  
Michal Baniyash ◽  
Juan S. Bonifacino ◽  
Lawrence E. Samelson
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Structure And Function ◽  
Zeta Chain ◽  
And Function

scholarly journals Potential impact of celiac disease genetic risk factors on T cell receptor signaling in gluten-specific CD4+ T cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Olivier B. Bakker ◽  
Aarón D. Ramírez-Sánchez ◽  
Zuzanna A. Borek ◽  
Niek de Klein ◽  
Yang Li ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Celiac Disease ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Transcriptional Response ◽  
Cell Receptor ◽  
Receptor Stimulation ◽  
Subsequent Activation

AbstractCeliac disease is an auto-immune disease in which an immune response to dietary gluten leads to inflammation and subsequent atrophy of small intestinal villi, causing severe bowel discomfort and malabsorption of nutrients. The major instigating factor for the immune response in celiac disease is the activation of gluten-specific CD4+ T cells expressing T cell receptors that recognize gluten peptides presented in the context of HLA-DQ2 and DQ8. Here we provide an in-depth characterization of 28 gluten-specific T cell clones. We assess their transcriptional and epigenetic response to T cell receptor stimulation and link this to genetic factors associated with celiac disease. Gluten-specific T cells have a distinct transcriptional profile that mostly resembles that of Th1 cells but also express cytokines characteristic of other types of T-helper cells. This transcriptional response appears not to be regulated by changes in chromatin state, but rather by early upregulation of transcription factors and non-coding RNAs that likely orchestrate the subsequent activation of genes that play a role in immune pathways. Finally, integration of chromatin and transcription factor binding profiles suggest that genes activated by T cell receptor stimulation of gluten‑specific T cells may be impacted by genetic variation at several genetic loci associated with celiac disease.

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