scholarly journals Identification, crystallization and epitope determination of public TCR shared and expanded in COVID-19 patients

2021 ◽  
Author(s):  
Xiuyuan Lu ◽  
Yuki Hosono ◽  
Shigenari Ishizuka ◽  
Masamichi Nagae ◽  
Eri Ishikawa ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Receptor ◽  
Protective Immunity ◽  
Cell Receptor ◽  
Symbiotic Bacteria ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Hla Dr ◽  
Human Coronaviruses

T cells play pivotal roles in protective immunity against SARS-CoV-2 infection. Follicular helper T (Tfh) cells mediate the production of antigen-specific antibodies; however, T cell receptor (TCR) clonotypes used by SARS-CoV-2-specific Tfh cells have not been well characterized. Here, we first identified and crystallized public TCR of Tfh clonotypes that are shared and expanded in unhospitalized COVID-19-recovered patients. These clonotypes preferentially recognized SARS-CoV-2 spike (S) protein epitopes which are conserved among emerging SARS-CoV-2 variants. These clonotypes did not react with S proteins derived from common cold human coronaviruses, but cross-reacted with symbiotic bacteria, which might confer the publicity. Among SARS-CoV-2 S epitopes, S864-882, presented by frequent HLA-DR alleles, could activate multiple public Tfh clonotypes in COVID-19-recovered patients. Furthermore, S864-882-loaded HLA tetramer preferentially bound to CD4+ T cells expressing CXCR5. In this study, we identified and crystallized public TCR for SARS-CoV-2 that may contribute to the prevention of COVID-19 aggravation.

scholarly journals High-resolution repertoire analysis of Tfr and Tfh cells reveals unexpectedly high diversities indicating a bystander activation of follicular T cells

2017 ◽  
Author(s):  
Paul-Gydéon Ritvo ◽  
Wahiba Chaara ◽  
Karim El Soufi ◽  
Benjamin Bonnet ◽  
Adrien Six ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Antibody Production ◽  
Cell Activation ◽  
Cell Receptor ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Tcr Repertoire ◽  
Self Antigen

ABSTRACTT follicular helper (Tfh) and regulatory (Tfr) cells regulate B cell activation and ultimately antibody production. While concordant results show that Tfh cells are specific for the immunizing antigens, limited and even controversial results have been reported regarding the specificity of Tfr cells. Here we used high-throughput T cell receptor (TCR) sequencing to address this issue. We observed that although the Tfh- and Tfr-cell repertoires are less diverse than those of effector (Teff) and regulatory T (Treg) cells, they still represent thousands of clonotypes after immunization with a single antigen. T-cell receptor beta variable (TRBV) gene usage distinguishes both follicular T cells (Tfol) from non-Tfol cells, as well as helper (Teff and Tfh) vs. regulatory (Treg and Tfr) cells. Analysis of the sharing of clonotypes between samples revealed that a specific response to the immunizing antigen can only be detected in Tfh cells immunized with a non-self-antigen and Tfr cells immunized with a self-antigen. Finally, the Tfr TCR repertoire is more similar to that of Tregs than to that of Tfh or Teff cells. Altogether, our results highlight a bystander Tfol-cell activation during antigenic response in the germinal centres and support the Treg cell origin of Tfr cells.Significance StatementFollicular helper T (Tfh) cells promote high-affinity antibody production by B cells while follicular regulatory T (Tfr) cells represses it. The question of the specificity of follicular T (Tfol) cells is of utmost importance in the understanding of the antibody response specificity and our work is the first to analysed the global Tfol TCR repertoire in wild type mice. This allowed us not only to portray the overall global structure of these repertoires, but also to substantiate the fact that Tfr cells respond to self-antigen while Tfh cells respond to non self-antigen, a still controversial issue. Importantly, our work revealed an unexpected bystander activation of Tfol cells. We think and discuss that it has a general significance in immune responses and possibly immunopathologies.

Acquisition of FOXP3 Expression by Human Effector CD4+ T Cells Is a Natural Consequence of Antigen Recognition.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 870-870
Author(s):  
J. Joseph Melenhorst ◽  
Phillip Scheinberg ◽  
David R. Ambrozak ◽  
Nancy F. Hensel ◽  
Daniel C. Douek ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Foxp3 Expression ◽  
Cell Receptor ◽  
Antigen Recognition ◽  
Natural Consequence ◽  
Antigen Stimulation ◽  
Hla Dr

Abstract Recent data suggest that CD4+CD25+FOXP3+ regulatory T cells (TR) can be generated from CD4+CD25−FOXP3− T cells in the periphery. We studied the induction of CD4+CD25+FOXP3+ T cells during the course of immune responses to cytomegalovirus, tetanus toxoid, purified protein derivative and streptokinase. Peripheral blood mononuclear cells (PBMC) from healthy donors were labeled with carboxyfluorescein diacetate, succinimidyl ester (CFDA) and stimulated with antigen for 6–7 days. Cells were stained for CD3, CD4, CD25, HLA-DR, CD38, and intracellular FOXP3. Responders to antigens had proliferating (CFDA[dim]) CD4+ T cells expressing CD25 and the activation markers CD38 and HLA-DR. In PBMC from five donors, a median of 37% (range 9–57%) of the proliferating fraction expressed FOXP3 (figure) which mostly co-expressed CD25, HLA-DR and CD38, suggesting that FOXP3 expression is the consequence of cellular activation triggered through the T cell receptor. Since all of these healthy subjects had circulating, pre-existing CD4+CD25+FOXP3+ T cells in the absence of ex vivo antigen stimulation, however, it was possible that these gave rise to the FOXP3+ responder cells. Antigen stimulation of PBMC from three donors aged 69–70 years with no detectable CD4+CD25+FOXP3+ T cells also induced proliferating activated CD4+CD25+FOXP3+ T cells, excluding the possibility that a pre-existing pool of FOXP3+ T cells gave rise to this population. Subsequently, we sorted CD4+ T cells that proliferated in response to antigen by flow cytometry on the basis of FOXP3 expression to sequence the T cell receptor-β CDR3 regions and to establish the T cell clonotype structure of proliferating FOXP3-positive and -negative T cells. These data also indicate that effector CD4+ T cells acquire FOXP3 expression during the course of an immune response. Based on these and previously reported findings, we propose that the acquisition of FOXP3 expression by effector CD4+ T cells is a natural consequence of antigen recognition that serves as a specific regulatory feedback system. Induction of FOXP3 expression in proliferating CD4+ T cells in response to T cell receptor triggering Induction of FOXP3 expression in proliferating CD4+ T cells in response to T cell receptor triggering

scholarly journals Synergistic T cell activation via the physiological ligands for CD2 and the T cell receptor.

1988 ◽  
Vol 168 (3) ◽  
pp. 1145-1156 ◽  
Author(s):  
B E Bierer ◽  
A Peterson ◽  
J C Gorga ◽  
S H Herrmann ◽  
S J Burakoff
Keyword(s):  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
Cell Surface ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Cytoplasmic Domain ◽  
Hla Dr

T cells may be activated either by the antigen-specific T cell receptor (TCR)-CD3 complex or the cell surface receptor CD2. A natural ligand for CD2 has been found to be lymphocyte function-associated antigen 3 (LFA-3), a widely distributed cell surface glycoprotein. To investigate the interaction of these two pathways, we have expressed the cDNA encoding the human CD2 molecule in a murine T cell hybridoma that produces IL-2 in response to HLA-DR antigens. Expression of the CD2 molecule markedly enhances IL-2 production in response to LFA-3+ antigen-bearing stimulator cells, and this stimulation is inhibited by anti-CD2 and anti-LFA-3 mAb. To further define the role of LFA-3 in antigen-dependent T cell activation, we have studied the ability of the purified ligands of CD2 and the TCR to stimulate the hybridoma. Neither liposomes containing purified HLA-DR antigens nor liposomes containing purified LFA-3 were able to stimulate the parent or the CD2+ hybridoma. However, liposomes containing both purified LFA-3 and HLA-DR, the physiological ligands for CD2 and the TCR, respectively, stimulate IL-2 production by the CD2+ but not the parent hybridoma, suggesting that complementary interactions between the TCR-CD3 complex and the CD2 pathway may regulate lymphocyte activation. To determine whether the CD2/LFA-3 interaction participates in cell-cell adhesion and provides an activation signal, we have constructed a cytoplasmic deletion mutant of CD2, CD2 delta B, in which the COOH-terminal 100 amino acids of CD2 have been replaced with a serine. Hybridomas expressing the CD2 delta B molecule were examined. Deletion of the cytoplasmic domain of CD2 did not alter binding of LFA-3 but eliminated the ability of CD2 to increase the response of the hybridoma to liposomes containing both HLA-DR and LFA-3, demonstrating that adhesion of LFA-3 to CD2 alone was insufficient for activation, and that the cytoplasmic domain was required for LFA-3 stimulation through the CD2 molecule. T cells may be activated by purified LFA-3 binding to CD2 and the TCR interacting with its ligand, and these signals appear to be synergistic for the T cell. These results suggest that the CD2/LFA-3 interaction not only plays a role in cell-cell adhesion but provides a stimulatory signal for T cell activation.

scholarly journals Opposing effects of T cell receptor signal strength on CD4 T cells responding to acute versus chronic viral infection

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Marco Künzli ◽  
Peter Reuther ◽  
Daniel D Pinschewer ◽  
Carolyn G King
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Signal Strength ◽  
Cell Receptor ◽  
Peptide Ligand ◽  
Altered Peptide Ligand ◽  
Tfh Cells ◽  
Wide Range

A hallmark of adaptive immunity is CD4 T cells’ ability to differentiate into specialized effectors. A long-standing question is whether T cell receptor (TCR) signal strength can dominantly instruct the development of Th1 and T follicular helper (Tfh) cells across distinct infectious contexts. We characterized the differentiation of murine CD4 TCR transgenic T cells responding to altered peptide ligand lymphocytic choriomeningitis viruses (LCMV) derived from acute and chronic parental strains. We found that TCR signal strength exerts opposite and hierarchical effects on the balance of Th1 and Tfh cells responding to acute versus persistent infection. TCR signal strength correlates positively with Th1 generation during acute but negatively during chronic infection. Weakly activated T cells express lower levels of markers associated with chronic T cell stimulation and may resist functional inactivation. We anticipate that the panel of recombinant viruses described herein will be valuable for investigating a wide range of CD4 T cell responses.

scholarly journals Human gamma delta T-cell receptor-positive cell-mediated inhibition of erythropoiesis in vitro in a patient with type I autoimmune polyglandular syndrome and pure red blood cell aplasia [see comments]

Blood ◽  
1990 ◽  
Vol 75 (4) ◽  
pp. 941-950
Author(s):  
T Hara ◽  
Y Mizuno ◽  
M Nagata ◽  
Y Okabe ◽  
S Taniguchi ◽  
...  
Keyword(s):  
T Cells ◽  
Blood Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Type I ◽  
Gamma Delta ◽  
Autoimmune Polyglandular Syndrome ◽  
Hla Dr ◽  
Alpha Beta ◽  
Gamma Delta T Cell

The gamma delta T-cell receptor-positive (gamma delta TCR+) lymphocytes were markedly expanded up to 68% of peripheral blood lymphocytes in a case with type I autoimmune polyglandular syndrome and pure red blood cell aplasia (PRCA). The gamma delta TCR+ cells showed CD4 negative, 16% dim-CD8 positive and 10% to 46% human leukocyte antigen-D-related (HLA-DR) positive, and exhibited no monoclonality as assessed by the patterns of TCR gene rearrangements. Functional studies revealed that the proliferative responses of the patient's peripheral blood mononuclear cells (PBMC) were severely depressed to candida antigen, alloantigens, and autoantigens (non-T cells). The gamma delta TCR+ cells had no suppressive effect on the proliferative response of the alpha beta TCR+ cells to candida. The patient's PBMC, isolated gamma delta TCR+ cells but not alpha beta TCR+ cells, exhibited non-major histocompatibility complex (MHC)-restricted cytotoxicity. Furthermore, the patient's PBMC and isolated gamma delta TCR+ cells inhibited burst- forming units-erythroid (BFU-E), but not colony-forming units/granulocyte-macrophage (CFU-GM). Supernatants derived from the patient's T cells similarly inhibited BFU-E but not CFU-GM. The clinical course of the patient also showed a close correlation between the decreased number of total lymphocyte counts, especially HLA-DR + gamma delta TCR+ cell counts, and recovery from PRCA. These observations suggest that the gamma delta TCR+ cells might be functional in vivo and involved in the pathogenesis of PRCA in this patient.

scholarly journals Human gamma delta T-cell receptor-positive cell-mediated inhibition of erythropoiesis in vitro in a patient with type I autoimmune polyglandular syndrome and pure red blood cell aplasia [see comments]

Blood ◽  
1990 ◽  
Vol 75 (4) ◽  
pp. 941-950 ◽  
Author(s):  
T Hara ◽  
Y Mizuno ◽  
M Nagata ◽  
Y Okabe ◽  
S Taniguchi ◽  
...  
Keyword(s):  
T Cells ◽  
Blood Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Type I ◽  
Gamma Delta ◽  
Autoimmune Polyglandular Syndrome ◽  
Hla Dr ◽  
Alpha Beta ◽  
Gamma Delta T Cell

Abstract The gamma delta T-cell receptor-positive (gamma delta TCR+) lymphocytes were markedly expanded up to 68% of peripheral blood lymphocytes in a case with type I autoimmune polyglandular syndrome and pure red blood cell aplasia (PRCA). The gamma delta TCR+ cells showed CD4 negative, 16% dim-CD8 positive and 10% to 46% human leukocyte antigen-D-related (HLA-DR) positive, and exhibited no monoclonality as assessed by the patterns of TCR gene rearrangements. Functional studies revealed that the proliferative responses of the patient's peripheral blood mononuclear cells (PBMC) were severely depressed to candida antigen, alloantigens, and autoantigens (non-T cells). The gamma delta TCR+ cells had no suppressive effect on the proliferative response of the alpha beta TCR+ cells to candida. The patient's PBMC, isolated gamma delta TCR+ cells but not alpha beta TCR+ cells, exhibited non-major histocompatibility complex (MHC)-restricted cytotoxicity. Furthermore, the patient's PBMC and isolated gamma delta TCR+ cells inhibited burst- forming units-erythroid (BFU-E), but not colony-forming units/granulocyte-macrophage (CFU-GM). Supernatants derived from the patient's T cells similarly inhibited BFU-E but not CFU-GM. The clinical course of the patient also showed a close correlation between the decreased number of total lymphocyte counts, especially HLA-DR + gamma delta TCR+ cell counts, and recovery from PRCA. These observations suggest that the gamma delta TCR+ cells might be functional in vivo and involved in the pathogenesis of PRCA in this patient.

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