scholarly journals Molecular basis of a dominant SARS-CoV-2 Spike-derived epitope presented by HLA-A*02:01 recognised by a public TCR

2021 ◽  
Author(s):  
Christopher Szeto ◽  
Andrea T Nguyen ◽  
Christian A Lobos ◽  
Dimitra SM Chatzileontiadou ◽  
Dhilshan Jayasinghe ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Molecular Basis ◽  
Cell Epitope ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
T Cell Response ◽  
X Ray Crystallography ◽  
Gene Usage

The data currently available on how the immune system recognizes the SARS-CoV-2 virus is growing rapidly. While there are structures of some SARS-CoV-2 proteins in complex with antibodies, which helps us understand how the immune system is able to recognise this new virus, we are lacking data on how T cells are able to recognize this virus. T cells, especially the cytotoxic CD8+ T cells, are critical for viral recognition and clearance. Here we report the X-ray crystallography structure of a T cell receptor, shared among unrelated individuals (public TCR) in complex with a dominant spike-derived CD8+ T cell epitope (YLQ peptide). We show that YLQ activates a polyfunctional CD8+ T cell response in COVID-19 recovered patients. We detail the molecular basis for the shared TCR gene usage observed in HLA-A*02:01+ individuals, providing an understanding of TCR recognition towards a SARS-CoV-2 epitope. Interestingly, the YLQ peptide conformation did not change upon TCR binding, facilitating the high-affinity interaction observed.

scholarly journals Molecular Basis of a Dominant SARS-CoV-2 Spike-Derived Epitope Presented by HLA-A*02:01 Recognised by a Public TCR

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2646
Author(s):  
Christopher Szeto ◽  
Andrea T. Nguyen ◽  
Christian A. Lobos ◽  
Demetra S. M. Chatzileontiadou ◽  
Dhilshan Jayasinghe ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Molecular Basis ◽  
Cell Epitope ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
T Cell Response ◽  
X Ray Crystallography ◽  
Gene Usage

The data currently available on how the immune system recognises the SARS-CoV-2 virus is growing rapidly. While there are structures of some SARS-CoV-2 proteins in complex with antibodies, which helps us understand how the immune system is able to recognise this new virus; however, we lack data on how T cells are able to recognise this virus. T cells, especially the cytotoxic CD8+ T cells, are critical for viral recognition and clearance. Here we report the X-ray crystallography structure of a T cell receptor, shared among unrelated individuals (public TCR) in complex with a dominant spike-derived CD8+ T cell epitope (YLQ peptide). We show that YLQ activates a polyfunctional CD8+ T cell response in COVID-19 recovered patients. We detail the molecular basis for the shared TCR gene usage observed in HLA-A*02:01+ individuals, providing an understanding of TCR recognition towards a SARS-CoV-2 epitope. Interestingly, the YLQ peptide conformation did not change upon TCR binding, facilitating the high-affinity interaction observed.

scholarly journals Predominant T cell receptor V gene usage in patients with abnormal clones of B cells

Blood ◽  
1991 ◽  
Vol 77 (8) ◽  
pp. 1776-1780 ◽  
Author(s):  
CH Janson ◽  
J Grunewald ◽  
A Osterborg ◽  
H DerSimonian ◽  
MB Brenner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Receptor ◽  
Gene Segment ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Gene Usage ◽  
V Gene

We have examined alpha/beta V gene segment usage of peripheral blood CD4+ and CD8+ T cells, respectively, from patients with multiple myeloma and monoclonal gammopathy of undetermined significance, by using T cell receptor (TCR) for antigen monoclonal antibodies (MoAbs). In 7 of 16 patients we found an increase in the usage of various TCR V gene segments. The expansion was confined to either the CD4+ or the CD8+ T-cell subset, except for one patient where an abnormal pattern was observed both within the CD4+ and CD8+ T-cell subsets. In one patient 47%, and in another patient 30% of the CD8+ lymphocytes reacted with alpha V12.1 and beta V6.7 antibodies, respectively. In two other patients 29% and 40% of the CD4+ lymphocytes reacted with beta V6.7 and beta V8.1 antibodies, respectively. We conclude that T cells with a predominant V gene usage is a frequent feature in patients with abnormal clonal B cells of malignant or benign types. T- and B-cell populations are normally clonally linked in regulatory circuits. An abnormal proliferation of B cells might therefore induce, or be regulated by, an expansion of clonal T cells, as suggested by the present results.

scholarly journals T cell receptor gene usage in the response to lambda repressor cI protein. An apparent bias in the usage of a V alpha gene element.

1988 ◽  
Vol 168 (3) ◽  
pp. 1081-1097 ◽  
Author(s):  
M Z Lai ◽  
S Y Huang ◽  
T J Briner ◽  
J G Guillet ◽  
J A Smith ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Receptor Gene ◽  
Cell Receptor ◽  
T Cell Response ◽  
Single Amino Acid ◽  
Clear Correlation ◽  
Antigen Specificity ◽  
Lambda Repressor ◽  
Gene Usage

The T cell response to the lambda repressor cI protein is directed to the same region of the protein (residues 12-26) in both BALB/c and A/J mice. A panel of T cell hybridomas specific for P12-26 in the context of either I-Ek or I-Ad have been isolated To further understand the molecular interaction between the TCR and the Ia-P12-26 complex, the primary structures of the TCR of five T cell hybridomas have been determined. Southern and Northern analyses indicate that two members of the V alpha 3 gene family are used by 13 out of 14 I-Ek-restricted T cells. Four different V beta genes are used by these T cell hybridomas, while the majority (8 out of 13) express V beta 1 in combination with the J beta 2.1 element. No clear correlation can be seen in this system between gene usage and MHC restriction. In addition, the fine specificity of I-Ek-restricted T cells to a single amino acid substitution [Phe22/His22]P12-26 is not attributed to the usage of particular V alpha and V beta elements. The V alpha 3 family gene is also used by a few I-Ad-restricted T cells. Interestingly, these I-Ad T cells share a reactivity pattern more similar to that of I-Ek-restricted T cells than other I-Ad-restricted T cells. The nonrandom selection V alpha 3 is also demonstrated by the fact that V alpha 3 is used by P12-26-specific, but not by cytochrome c- or staphylococcal nucleus-specific, I-Ek-restricted T cells. This suggests that although antigen specificity may not be accounted for by either chain of the TCR, the members of V alpha 3 genes may be selected by the antigen (P12-26).

The only proposed T-cell epitope derived from the TEL-AML1 translocation is not naturally processed

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 946-954 ◽  
Author(s):  
Jelena Popović ◽  
Liang-Ping Li ◽  
Peter Michael Kloetzel ◽  
Matthias Leisegang ◽  
Wolfgang Uckert ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Cell Epitope ◽  
Chimeric Protein ◽  
Chromosomal Translocation ◽  
Cell Receptor ◽  
T Cell Response ◽  
Adoptive Therapy

Abstract Adoptive therapy with T-cell receptor (TCR)–engineered T cells is a promising approach in cancer treatment. While usage of T cells specific for tumor-associated antigens (TAAs) can lead to serious side effects because of autoimmunity, targeting true tumor-specific mutations, such as the products of translocations in leukemias, should reduce such a risk. A potentially ideal target might be the chimeric protein TEL-AML1, which results from the chromosomal translocation 12;21 and represents the most common fusion gene in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Within the fusion region of TEL-AML1, a single epitope has been described by reverse immunology as immunogenic in HLA-A*0201 restriction settings. As a potential source of TCRs specific for this TEL-AML1 epitope, we have used mice expressing a human TCR-αβ repertoire and human MHC class I. Surprisingly, we have found that, although a specific functional CD8+ T-cell response against this peptide could be evoked, the described epitope was in fact not endogenously processed. Analyses done with a potent antigen-presenting cell line, as well as with purified human proteasomes, support the conclusion that this peptide cannot be proposed as a potential target in immunotherapy of ALL in HLA-A*0201-restricted fashion.

scholarly journals Human fetuses are able to mount an adultlike CD8 T-cell response

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2153-2158 ◽  
Author(s):  
Emmanuel Hermann ◽  
Carine Truyens ◽  
Cristina Alonso-Vega ◽  
Jos Even ◽  
Patricia Rodriguez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Interferon Γ ◽  
T Cell Response ◽  
Activation Markers ◽  
T Cell Receptor Beta

Abstract Fetal/neonatal immune responses generally are considered to be immature and weaker than that of adults. We have studied the cord-blood T cells of newborns congenitally infected with Trypanosoma cruzi, the protozoan agent of Chagas disease. Our data demonstrate a predominant activation of CD8 T cells expressing activation markers and armed to mediate effector functions. The analysis of the T-cell receptor beta chain variable repertoire shows the oligoclonal expansion of these T lymphocytes, indicating that activation was driven by parasite antigens. Indeed, we have detected parasite-specific CD8 T cells secreting interferon-γ after coincubation with live T cruzi. This response is enhanced in the presence of recombinant interleukin-15, which limits the T-cell spontaneous apoptosis. These findings point out that the fetal immune system is more competent than previously appreciated, since fetuses exposed to live pathogens are able to develop an adultlike immune CD8 T-cell response.

scholarly journals Rapid selection and identification of functional CD8+ T cell epitopes from large peptide-coding libraries

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Govinda Sharma ◽  
Craig M. Rive ◽  
Robert A. Holt
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Epitope ◽  
Cell Receptor ◽  
T Cell Response ◽  
Target Cells ◽  
T Cell Epitopes ◽  
Peptide Epitopes ◽  
Histocompatibility Complex

Abstract Cytotoxic CD8+ T cells recognize and eliminate infected or malignant cells that present peptide epitopes derived from intracellularly processed antigens on their surface. However, comprehensive profiling of specific major histocompatibility complex (MHC)-bound peptide epitopes that are naturally processed and capable of eliciting a functional T cell response has been challenging. Here, we report a method for deep and unbiased T cell epitope profiling, using in vitro co-culture of CD8+ T cells together with target cells transduced with high-complexity, epitope-encoding minigene libraries. Target cells that are subject to cytotoxic attack from T cells in co-culture are isolated prior to apoptosis by fluorescence-activated cell sorting, and characterized by sequencing the encoded minigenes. We then validate this highly parallelized method using known murine T cell receptor/peptide-MHC pairs and diverse minigene-encoded epitope libraries. Our data thus suggest that this epitope profiling method allows unambiguous and sensitive identification of naturally processed and MHC-presented peptide epitopes.

scholarly journals Human fetuses are able to mount an adultlike CD8 T-cell response

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2153-2158
Author(s):  
Emmanuel Hermann ◽  
Carine Truyens ◽  
Cristina Alonso-Vega ◽  
Jos Even ◽  
Patricia Rodriguez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Interferon Γ ◽  
T Cell Response ◽  
Activation Markers ◽  
T Cell Receptor Beta

Fetal/neonatal immune responses generally are considered to be immature and weaker than that of adults. We have studied the cord-blood T cells of newborns congenitally infected with Trypanosoma cruzi, the protozoan agent of Chagas disease. Our data demonstrate a predominant activation of CD8 T cells expressing activation markers and armed to mediate effector functions. The analysis of the T-cell receptor beta chain variable repertoire shows the oligoclonal expansion of these T lymphocytes, indicating that activation was driven by parasite antigens. Indeed, we have detected parasite-specific CD8 T cells secreting interferon-γ after coincubation with live T cruzi. This response is enhanced in the presence of recombinant interleukin-15, which limits the T-cell spontaneous apoptosis. These findings point out that the fetal immune system is more competent than previously appreciated, since fetuses exposed to live pathogens are able to develop an adultlike immune CD8 T-cell response.

scholarly journals In chronic infection, HIV gag-specific CD4+ T cell receptor diversity is higher than CD8+ T cell receptor diversity and is associated with less HIV quasispecies diversity

2021 ◽  
Author(s):  
Mark A Pilkinton ◽  
Wyatt J McDonnell ◽  
Louise Barnett ◽  
Abha Chopra ◽  
Rama Gangula ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Tcr Repertoire ◽  
Tcr Diversity

Cellular immune responses to Gag correlate with improved HIV viral control. The full extent of cellular immune responses comprise both the number of epitopes recognized by CD4+ and CD8+ T cells, as well as the diversity of the T cell receptor (TCR) repertoire directed against each epitope. The optimal diversity of the responsive TCR repertoire is unclear. Therefore, we evaluated the TCR diversity of CD4+ and CD8+ T cells responding to HIV-1 Gag to determine if TCR diversity correlates with clinical or virologic metrics. Previous studies of TCR repertoires have been limited primarily to CD8+ T cell responses directed against a small number of well-characterized T cell epitopes restricted by specific human leucocyte antigens. We stimulated peripheral blood mononuclear cells from 21chronic HIV-infected individuals overnight with a pool of HIV-1 Gag peptides, followed by sorting of activated CD4+ and CD8+ T cells and TCR deep sequencing. We found Gag-reactive CD8+ T cells to be more oligoclonal, with a few dominant TCRs comprising the bulk of the repertoire, compared to the highly diverse TCR repertoires of Gag-reactive CD4+ T cells. HIV viral sequencing of the same donors revealed that high CD4+ T cell TCR diversity was strongly associated with lower HIV Gag genetic diversity. We conclude that the TCR repertoire of Gag-reactive CD4+ T helper cells display substantial diversity without a clearly dominant circulating TCR clonotype, in contrast to a hierarchy of dominant TCR clonotypes in the Gag-reactive CD8+ T cells, and may serve to limit HIV diversity during chronic infection. IMPORTANCE Human T cells recognize portions of viral proteins bound to host molecules (human leucocyte antigens) on the surface of infected cells. T cells recognize these foreign proteins through their T cell receptors (TCRs), which are formed by the assortment of several available V, D and J genes to create millions of combinations of unique TCRs. We measured the diversity of T cells responding to the HIV Gag protein. We found the CD8+ T cell response is primarily made up of a few dominant unique TCRs whereas the CD4+ T cell subset has a much more diverse repertoire of TCRs. We also found there was less change in the virus sequences in subjects with more diverse TCR repertoires. HIV has a high mutation rate, which allows it to evade the immune response. Our findings describe the characteristics of a virus-specific T cell response that may allow it to limit viral evolution.

scholarly journals Predominant T cell receptor V gene usage in patients with abnormal clones of B cells

Blood ◽  
1991 ◽  
Vol 77 (8) ◽  
pp. 1776-1780 ◽  
Author(s):  
CH Janson ◽  
J Grunewald ◽  
A Osterborg ◽  
H DerSimonian ◽  
MB Brenner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Receptor ◽  
Gene Segment ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Gene Usage ◽  
V Gene

Abstract We have examined alpha/beta V gene segment usage of peripheral blood CD4+ and CD8+ T cells, respectively, from patients with multiple myeloma and monoclonal gammopathy of undetermined significance, by using T cell receptor (TCR) for antigen monoclonal antibodies (MoAbs). In 7 of 16 patients we found an increase in the usage of various TCR V gene segments. The expansion was confined to either the CD4+ or the CD8+ T-cell subset, except for one patient where an abnormal pattern was observed both within the CD4+ and CD8+ T-cell subsets. In one patient 47%, and in another patient 30% of the CD8+ lymphocytes reacted with alpha V12.1 and beta V6.7 antibodies, respectively. In two other patients 29% and 40% of the CD4+ lymphocytes reacted with beta V6.7 and beta V8.1 antibodies, respectively. We conclude that T cells with a predominant V gene usage is a frequent feature in patients with abnormal clonal B cells of malignant or benign types. T- and B-cell populations are normally clonally linked in regulatory circuits. An abnormal proliferation of B cells might therefore induce, or be regulated by, an expansion of clonal T cells, as suggested by the present results.

scholarly journals Antiviral Cd8+ T Cell Responses in Neonatal Mice

2001 ◽  
Vol 193 (5) ◽  
pp. 595-606 ◽  
Author(s):  
Janice M. Moser ◽  
John D. Altman ◽  
Aron E. Lukacher
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Acute Infection ◽  
Cell Epitope ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Polyoma Virus ◽  
Newborn Mice

Polyoma virus is a potent oncogenic pathogen when inoculated into newborn mice of particular H-2k strains. Using Dk tetramers containing the dominant antipolyoma CD8+ T cell epitope, middle T protein (MT)389–397, and intracellular interferon γ staining, we enumerated MT389-specific CD8+ T cells in infected neonates having opposite susceptibilities to polyoma virus–induced tumors. In resistant mice, MT389-specific CD8+ T cells dramatically expanded during acute infection in neonates to a frequency rivaling that in adults; furthermore, in both neonatal and adult mice, this antipolyoma CD8+ T cell response exhibited nearly identical T cell receptor (TCR) functional avidities and TCR functional fingerprints. Susceptible mice mounted an MT389-specific CD8+ T cell response of only fourfold lower magnitude than resistant mice; but, in clear contrast to resistant mice, these CD8+ T cells lacked ex vivo MT389-specific cytotoxic activity. However, MT389-specific CD8+ T cells in resistant and susceptible mice expressed similar TCR avidities, perforin levels, and surface type O-glycan levels indicative of mature CD8+ T cell effectors. Upon in vitro restimulation with infected antigen-presenting cells, CD8+ T cells from acutely infected susceptible neonates acquired strong MT389-specific cytotoxicity. These findings indicate that polyoma-specific CD8+ T cells are armed with, but restrained from deploying, their cytotoxic effector function in mice susceptible to polyoma virus tumorigenesis.

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