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

scholarly journals T Cell Receptor (Tcr)-Mediated Repertoire Selection and Loss of Tcr Vβ Diversity during the Initiation of a Cd4+ T Cell Response in Vivo

2000 ◽  
Vol 192 (12) ◽  
pp. 1719-1730 ◽  
Author(s):  
Marcella Fassò ◽  
Niroshana Anandasabapathy ◽  
Frances Crawford ◽  
John Kappler ◽  
C. Garrison Fathman ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Repertoire Selection

We recently described a novel way to isolate populations of antigen-reactive CD4+ T cells with a wide range of reactivity to a specific antigen, using immunization with a fixed dose of nominal antigen and FACS® sorting by CD4high expression. Phenotypic, FACS®, functional, antibody inhibition, and major histocompatibility complex–peptide tetramer analyses, as well as T cell receptor Vβ sequence analyses, of the antigen-specific CD4high T cell populations demonstrated that a diverse sperm whale myoglobin 110–121–reactive CD4+ T cell repertoire was activated at the beginning (day 3 after immunization) of the immune response. Within 6 d of immunization, lower affinity clones were lost from the responding population, leaving an expanded population of oligoclonal, intermediate affinity (and residual high affinity) T cells. This T cell subset persisted for at least 4 wk after immunization and dominated the secondary immune response. These data provide evidence that CD4+ T cell repertoire selection occurs early in the immune response in vivo and suggest that persistence and expansion of a population of oligoclonal, intermediate affinity T cells is involved in CD4+ T cell memory.

CD4+ T cells specific for glycoprotein B from cytomegalovirus exhibit extreme conservation of T-cell receptor usage between different individuals

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2053-2061 ◽  
Author(s):  
Laura Crompton ◽  
Naeem Khan ◽  
Rajiv Khanna ◽  
Laxman Nayak ◽  
Paul A. H. Moss
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Response ◽  
Cd4 T Cells ◽  
Clonal Selection ◽  
Cell Receptor ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Extreme Conservation

Antigen-specific CD8+ cytotoxic T cells often demonstrate extreme conservation of T-cell receptor (TCR) usage between different individuals, but similar characteristics have not been documented for CD4+ T cells. CD4+ T cells predominantly have a helper immune role, but a cytotoxic CD4+ T-cell subset has been characterized, and we have studied the cytotoxic CD4+ T-cell response to a peptide from human cytomegalovirus glycoprotein B presented through HLA-DRB*0701. We show that this peptide elicits a cytotoxic CD4+ T-cell response that averages 3.6% of the total CD4+ T-cell repertoire of cytomegalovirus-seropositive donors. Moreover, CD4+ cytotoxic T-cell clones isolated from different individuals exhibit extensive conservation of TCR usage, which indicates strong T-cell clonal selection for peptide recognition. Remarkably, this TCR sequence was recently reported in more than 50% of cases of CD4+ T-cell large granular lymphocytosis. Immunodominance of cytotoxic CD4+ T cells thus parallels that of CD8+ subsets and suggests that cytotoxic effector function is critical to the development of T-cell clonal selection, possibly from immune competition secondary to lysis of antigen-presenting cells. In addition, these TCR sequences are highly homologous to those observed in HLA-DR7+ patients with CD4+ T-cell large granular lymphocytosis and implicate cytomegalovirus as a likely antigenic stimulus for this disorder.

scholarly journals Direct Expansion of Functional CD25+ CD4+ Regulatory T Cells by Antigen-processing Dendritic Cells

2003 ◽  
Vol 198 (2) ◽  
pp. 235-247 ◽  
Author(s):  
Sayuri Yamazaki ◽  
Tomonori Iyoda ◽  
Kristin Tarbell ◽  
Kara Olson ◽  
Klara Velinzon ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Antigen Processing ◽  
Specific Antigen ◽  
Cell Receptor ◽  
Cd4 T Cell

An important pathway for immune tolerance is provided by thymic-derived CD25+ CD4+ T cells that suppress other CD25− autoimmune disease–inducing T cells. The antigen-presenting cell (APC) requirements for the control of CD25+ CD4+ suppressor T cells remain to be identified, hampering their study in experimental and clinical situations. CD25+ CD4+ T cells are classically anergic, unable to proliferate in response to mitogenic antibodies to the T cell receptor complex. We now find that CD25+ CD4+ T cells can proliferate in the absence of added cytokines in culture and in vivo when stimulated by antigen-loaded dendritic cells (DCs), especially mature DCs. With high doses of DCs in culture, CD25+ CD4+ and CD25− CD4+ populations initially proliferate to a comparable extent. With current methods, one third of the antigen-reactive T cell receptor transgenic T cells enter into cycle for an average of three divisions in 3 d. The expansion of CD25+ CD4+ T cells stops by day 5, in the absence or presence of exogenous interleukin (IL)-2, whereas CD25− CD4+ T cells continue to grow. CD25+ CD4+ T cell growth requires DC–T cell contact and is partially dependent upon the production of small amounts of IL-2 by the T cells and B7 costimulation by the DCs. After antigen-specific expansion, the CD25+ CD4+ T cells retain their known surface features and actively suppress CD25− CD4+ T cell proliferation to splenic APCs. DCs also can expand CD25+ CD4+ T cells in the absence of specific antigen but in the presence of exogenous IL-2. In vivo, both steady state and mature antigen-processing DCs induce proliferation of adoptively transferred CD25+ CD4+ T cells. The capacity to expand CD25+ CD4+ T cells provides DCs with an additional mechanism to regulate autoimmunity and other immune responses.

scholarly journals Engineered FVIII-Specific Human T-Effector Cells: Can the T-Cell Receptor Modulate CD4+ T-Helper Phenotypes or Is It Just a “Switch”?

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1417-1417
Author(s):  
Patrick Adair ◽  
Yong Chan Kim ◽  
Kathleen P. Pratt ◽  
David W Scott
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Hemophilia A ◽  
Puget Sound ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
Dose Titration ◽  
T Helper

Abstract Engineered T cells are a vital component in the armamentarium of cellular therapies. In this presentation, we examine how human CD4+ T cells, genetically engineered to express a T-cell receptor (TCR) specific for a C2 domain epitope of the coagulation protein cofactor FVIII, can be skewed or polarized to different T-helper subsets. Two TCRs were cloned from Th2 and Th17/Th1 phenotyped CD4+ T cells isolated via a tetramer guided epitope mapping (TGEM) technique from a hemophilia A subject after clinical diagnosis of an inhibitor (neutralizing antibody) to FVIII given as replacement therapy. The two TCRs were cloned using a 5’ RACE with semi-nested PCR and transduced via a retroviral vector into healthy non-hemophilia A human donor CD4+ T cells. Based on proliferation and HLA class II tetramer staining data, engineered CD4+ T cells expressing the different cloned TCRs exhibited different avidities for the same C2 peptide (containing the epitope) over a dose titration curve, despite similar levels of TCR expression on the CD4 T-cell surface. IFN-γ, TNF-α, IL-6, and IL-10 cytokine production levels following stimulation with C2 peptide and DR1 antigen presenting cells, as measured by cytokine bead analysis, were significantly greater for the higher avidity TCR, which was cloned from a “Th2” phenotyped CD4+ T-cell clone. Interestingly, neither the engineered CD4+ T cells expressing the Th2 TCR nor the cells expressing the Th17/Th1 TCR produced cytokines characteristic of their respective original parental clones. Rather, they reflected the cytokine profiles of the donor populations used for transduction. These preliminary data led us to investigate how the different avidities of the two cloned TCRs can modulate the T-helper subset skewing/differentiation potential of engineered CD4+T cells. We hypothesized that the TCR is merely a switch that can activate or direct engineered CD4+ T cells to an antigen-specific response that would be skewed to the T-helper phenotypes of the cells prior to TCR transduction. We further hypothesized that this response could be modulated after TCR transduction according to the apparent tetramer avidity of the engineered cells. We successfully skewed the engineered human T-helper cells to Th1, Th2 and Th17 lineages, based on T-helper signature cytokine expression and the transcription factors T-bet, Gata3 and RORγt. Moreover, we observed that TCR transduction into naïve human CD4+ T cells did not itself affect the T-helper subset skewing of the cells. Preliminary experiments showed a trend toward Th2 skewing for the high avidity Th2 CD4+ T cells having an engineered TCR when they were cultured under either Th1 or Th2 polarizing conditions and stimulated with the C2 peptide, compared to the phenotypes obtained following stimulation of polyclonal CD4 T cells with anti-CD3. These studies will improve our designing of engineered TCRs for CD4+T-cell therapy, especially when concerns of T-helper effector function and plasticity are important to clinical outcomes. Supported by NIH RO1-HL061883 (DWS), funding from Bayer and CSL Behring (KPP) and intramural support from NIAID (EMS). We thank Dr. Arthur Thompson (Puget Sound Blood Center) for enrolling patients and we thank all blood donors. Disclosures No relevant conflicts of interest to declare.

scholarly journals CD4+ T cell subsets present stable relationships in their T cell receptor repertoires

2020 ◽  
Author(s):  
Shiyu Wang ◽  
Longlong Wang ◽  
Ya Liu
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Antigen Specificity ◽  
Sequence Composition

AbstractCD4+ T cells are key components of adaptive immunity. The cell differentiation equips CD4+ T cells with new functions. However, the effect of cell differentiation on T cell receptor (TCR) repertoire is not investigated. Here, we examined the features of TCR beta (TCRB) repertoire of the top clones within naïve, memory and regular T cell (Treg) subsets: repertoire structure, gene usage, length distribution and sequence composition. First, we found that memory subsets and Treg would be discriminated from naïve by the features of TCRB repertoire. Second, we found that the correlations between the features of memory subsets and naïve were positively related to differentiation levels of memory subsets. Third, we found that public clones presented a reduced proportion and a skewed sequence composition in differentiated subsets. Furthermore, we found that public clones led naïve to recognize a broader spectrum of antigens than other subsets. Our findings suggest that TCRB repertoire of CD4+ T cell subsets is skewed in a differentiation-depended manner. Our findings show that the variations of public clones contribute to these changes. Our findings indicate that the reduce of public clones in differentiation trim the antigen specificity of CD4+ T cells. The study unveils the physiological effect of memory formation and facilitates the selection of proper CD4+ subset for cellular therapy.

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 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.

scholarly journals Relaxation times of ligand-receptor complex formation control T cell activation

2019 ◽  
Author(s):  
Hamid Teimouri ◽  
Anatoly B. Kolomeisky
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Formation Control ◽  
Cell Activation ◽  
Relaxation Times ◽  
Cell Receptor ◽  
Stationary Concentration

AbstractOne of the most important functions of immune T cells is to recognize the presence of the pathogen-derived ligands and to quickly respond to them while at the same time not to respond to its own ligands. This is known as an absolute discrimination, and it is one of the most challenging phenomena to explain. The effectiveness of pathogen detection by T cell receptor (TCR) is limited by the chemical similarity of foreign and self-peptides and very low concentrations of foreign ligands. We propose a new mechanism of the absolute discrimination by T cells. It is suggested that the decision to activate or not to activate the immune response is controlled by the time to reach the stationary concentration of the TCR-ligand activated complex, which transfers the signal to downstream cellular biochemical networks. Our theoretical method models T-cell receptor phosphorylation events as a sequence of stochastic transitions between discrete biochemical states, and this allows us to explicitly describe the dynamical properties of the system. It is found that the proposed criterion on the relaxation times is able to explain available experimental observations. In addition, our theoretical approach explicitly analyzes the relationships between speed, sensitivity and specificity of the T cell functioning, which are the main characteristics of the process. Thus, it clarifies the molecular picture of the T cell activation processes in immune response.

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