scholarly journals Positive Selection of Cd4+ T Cells Is Induced in Vivo by Agonist and Inhibited by Antagonist Peptides

2001 ◽  
Vol 194 (4) ◽  
pp. 407-416 ◽  
Author(s):  
Piotr Kraj ◽  
Rafal Pacholczyk ◽  
Hanna Ignatowicz ◽  
Pawel Kisielow ◽  
Peter Jensen ◽  
...  
Keyword(s):  
T Cells ◽  
Positive Selection ◽  
Cd4 T Cells ◽  
In Vivo Model ◽  
Agonist Peptide ◽  
Histocompatibility Complex ◽  
Antagonist Peptides ◽  
Prevailing View ◽  
Selection Of

The nature of peptides that positively select T cells in the thymus remains poorly defined. Here we report an in vivo model to study the mechanisms of positive selection of CD4+ T cells. We have restored positive selection of TCR transgenic CD4+ thymocytes, arrested at the CD4+CD8+ stage, due to the lack of the endogenously selecting peptide(s), in mice deficient for H2-M and invariant chain. A single injection of soluble agonist peptide(s) initiated positive selection of CD4+ transgenic T cells that lasted for up to 14 days. Positively selected CD4+ T cells repopulated peripheral lymphoid organs and could respond to the antigenic peptide. Furthermore, coinjection of the antagonist peptide significantly inhibited agonist-driven positive selection. Hence, contrary to the prevailing view, positive selection of CD4+ thymocytes can be induced in vivo by agonist peptides and may be a result of accumulation of signals from TCR engaged by different peptides bound to major histocompatibility complex class II molecules. We have also identified a candidate natural agonist peptide that induces positive selection of CD4+ TCR transgenic thymocytes.

Functional comparison of thymic B cells and dendritic cells in vivo

Blood ◽  
2000 ◽  
Vol 95 (8) ◽  
pp. 2610-2616 ◽  
Author(s):  
Petra Kleindienst ◽  
Isabelle Chretien ◽  
Thomas Winkler ◽  
Thomas Brocker
Keyword(s):  
T Cells ◽  
B Cells ◽  
Positive Selection ◽  
B Lymphocytes ◽  
Cd4 T Cells ◽  
Cell Types ◽  
Class Ii ◽  
Histocompatibility Complex ◽  
Targeted Gene Expression

In this report we present a transgenic mouse model in which we targeted gene expression specifically to B-lymphocytes. Using the human CD19 promoter, we expressed major histocompatibility complex class II I-E molecules specifically on B cells of all tissues, but not on other cell types. If only B cells expressed I-E in a class II-deficient background, positive selection of CD4+ T cells could not be observed. A comparison of the frequencies of I-E reactive Vβ5+ and Vβ11+ T cells shows that I-E expression on thymic B cells is sufficient to negatively select I-E reactive CD4+ T cells partially, but not CD8+ T cells. Thus partial negative but no positive selection events can be induced by B-lymphocytes in vivo.

Functional comparison of thymic B cells and dendritic cells in vivo

Blood ◽  
2000 ◽  
Vol 95 (8) ◽  
pp. 2610-2616 ◽  
Author(s):  
Petra Kleindienst ◽  
Isabelle Chretien ◽  
Thomas Winkler ◽  
Thomas Brocker
Keyword(s):  
T Cells ◽  
B Cells ◽  
Positive Selection ◽  
B Lymphocytes ◽  
Cd4 T Cells ◽  
Cell Types ◽  
Class Ii ◽  
Histocompatibility Complex ◽  
Targeted Gene Expression

Abstract In this report we present a transgenic mouse model in which we targeted gene expression specifically to B-lymphocytes. Using the human CD19 promoter, we expressed major histocompatibility complex class II I-E molecules specifically on B cells of all tissues, but not on other cell types. If only B cells expressed I-E in a class II-deficient background, positive selection of CD4+ T cells could not be observed. A comparison of the frequencies of I-E reactive Vβ5+ and Vβ11+ T cells shows that I-E expression on thymic B cells is sufficient to negatively select I-E reactive CD4+ T cells partially, but not CD8+ T cells. Thus partial negative but no positive selection events can be induced by B-lymphocytes in vivo.

scholarly journals Targeted Expression of Major Histocompatibility Complex (MHC) Class II Molecules Demonstrates that Dendritic Cells Can Induce Negative but Not Positive Selection of Thymocytes In Vivo

1997 ◽  
Vol 185 (3) ◽  
pp. 541-550 ◽  
Author(s):  
Thomas Brocker ◽  
Mireille Riedinger ◽  
Klaus Karjalainen
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Major Histocompatibility Complex ◽  
Positive Selection ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Selection Of

It is well established that lymphoid dendritic cells (DC) play an important role in the immune system. Beside their role as potent inducers of primary T cell responses, DC seem to play a crucial part as major histocompatibility complex (MHC) class II+ “interdigitating cells” in the thymus during thymocyte development. Thymic DC have been implicated in tolerance induction and also by some authors in inducing major histocompatibility complex restriction of thymocytes. Most of our knowledge about thymic DC was obtained using highly invasive and manipulatory experimental protocols such as thymus reaggregation cultures, suspension cultures, thymus grafting, and bone marrow reconstitution experiments. The DC used in those studies had to go through extensive isolation procedures or were cultured with recombinant growth factors. Since the functions of DC after these in vitro manipulations have been reported to be not identical to those of DC in vivo, we intended to establish a system that would allow us to investigate DC function avoiding artificial interferences due to handling. Here we present a transgenic mouse model in which we targeted gene expression specifically to DC. Using the CD11c promoter we expressed MHC class II I-E molecules specifically on DC of all tissues, but not on other cell types. We report that I-E expression on thymic DC is sufficient to negatively select I-E reactive CD4+ T cells, and to a less complete extent, CD8+ T cells. In contrast, if only DC expressed I-E in a class II–deficient background, positive selection of CD4+ T cells could not be observed. Thus negative, but not positive, selection events can be induced by DC in vivo.

scholarly journals A Kinetic Threshold between Negative and Positive Selection Based on the Longevity of the T Cell Receptor–Ligand Complex

1999 ◽  
Vol 189 (10) ◽  
pp. 1531-1544 ◽  
Author(s):  
Calvin B. Williams ◽  
Deborah L. Engle ◽  
Gilbert J. Kersh ◽  
J. Michael White ◽  
Paul M. Allen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Positive Selection ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Ligand Complex ◽  
Altered Peptide Ligands ◽  
Self Peptides ◽  
Selection Of

We have developed a unique in vivo system to determine the relationship between endogenous altered peptide ligands and the development of major histocompatibility complex class II– restricted T cells. Our studies use the 3.L2 T cell receptor (TCR) transgenic mouse, in which T cells are specific for Hb(64–76)/I-Ek and positively selected on I-Ek plus self-peptides. To this endogenous peptide repertoire, we have individually added one of six well-characterized 3.L2 ligands. This transgenic approach expands rather than constrains the repertoire of self-peptides. We find that a broad range of ligands produce negative selection of thymocytes in vivo. When compared with the in vitro TCR–ligand binding kinetics, we find that these negatively selecting ligands all have a half-life of 2 s or greater. Additionally, one of two ligands examined with no detectable binding to the 3.L2 TCR and no activity on mature 3.L2 T cells (Q72) enhances the positive selection of transgenic thymocytes in vivo. Together, these data establish a kinetic threshold between negative and positive selection based on the longevity of TCR–ligand complexes.

Preferential expression of Vβ6.7 domain on human peripheral CD4+ T cells. Implication for positive selection of T cells in man

1991 ◽  
Vol 21 (6) ◽  
pp. 1571-1574 ◽  
Author(s):  
Andrea Cossarizza ◽  
Melvyn Kahan ◽  
Claudio Ortolani ◽  
Claudio Franceschi ◽  
Marco Londei
Keyword(s):  
T Cells ◽  
Positive Selection ◽  
Cd4 T Cells ◽  
Preferential Expression ◽  
Selection Of

scholarly journals A combination of cyclophosphamide, interleukin-2 allow CD4+ T cells converted to Tregs to control scurfy syndrome

Blood ◽  
2021 ◽  
Author(s):  
Marianne Delville ◽  
Florence Bellier ◽  
Juliette Leon ◽  
Roman Klifa ◽  
Sabrina Lizot ◽  
...  
Keyword(s):  
T Cells ◽  
Autoimmune Disease ◽  
Adoptive Transfer ◽  
Cd4 T Cells ◽  
Lentiviral Vector ◽  
Interleukin 2 ◽  
Foxp3 Expression ◽  
In Vivo Model ◽  
Loss Of Function

Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome is caused by mutations in FOXP3, which lead to the loss of function of regulatory T cells (Treg) and the development of autoimmune manifestations early in life. The selective induction of a Treg program in autologous CD4+ T cells by FOXP3 gene transfer is a promising approach for curing IPEX. We have established a novel in vivo assay of Treg functionality, based on adoptive transfer of these cells into scurfy mice (an animal model of IPEX) and a combination of cyclophosphamide conditioning and interleukin-2 treatment. This model highlighted the possibility of rescuing scurfy disease after the latter's onset. By using this in vivo model and an optimized lentiviral vector expressing human Foxp3 and as a reporter a truncated form of the 5 low-affinity nerve growth factor receptor (DLNGFR), we demonstrated that the adoptive transfer of FOXP3-transduced scurfy CD4+ T cells enabled the long-term rescue of scurfy autoimmune disease. The efficiency was similar to that seen with wild-type Treg. After in vivo expansion, the converted CD4FOXP3 cells recapitulated the transcriptomic core signature for Treg. These findings demonstrate that FOXP3 expression converts CD4+ T cells into functional Treg capable of controlling severe autoimmune disease.

Artificial Thymic Organoids Permit Allelic Exclusion and Efficient Generation of Naïve TCR-Engineered T-Cells from Human Hematopoietic Stem Cells In Vitro

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4553-4553
Author(s):  
Christopher S Seet ◽  
Chongbin He ◽  
Michael Bethune ◽  
Suwen Li ◽  
Brent Chick ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Intellectual Property ◽  
Positive Selection ◽  
Allelic Exclusion ◽  
Hematopoietic Stem ◽  
Engineered T Cells ◽  
Selection Of

Abstract Engineered adoptive immunotherapies have shown unprecedented activity in the treatment of cancer and chronic viral infections. Current approaches rely on individualized ex vivo genetic modification of autologous T cells due to the risk of graft-versus-host disease from allogeneic T cells. These processes furthermore require activation and prolonged expansion of T cells, which may reduce in vivo efficacy and persistence. Direct in vitro differentiation of engineered T cells from hematopoietic stem and progenitor cells (HSPCs) may overcome these problems by permitting the suppression of endogenous TCR expression through allelic exclusion, and the de novo generation of naïve antigen-specific T cells. Existing methods of in vitro human T cell differentiation are subject to wide experimental variability and do not adequately support the positive selection of immature T cell precursors to mature T cells, and thus have not been suitable for clinical-scale production of engineered T cells. We report here the preclinical development of an artificial thymic organoid (ATO) system using off-the-shelf, serum-free components and a standardized stromal cell line that supports highly efficient in vitro differentiation and positive selection of native and TCR-engineered human T cells from cord blood (CB), bone marrow, and mobilized peripheral blood CD34+ HSPCs, and purified CD34+CD38- hematopoietic stem cells. ATOs closely recapitulated thymic T cell commitment and differentiation, resulting in greater than 80% CD7+CD5+ T-lineage cells and 50% CD4+CD8+ double positive (DP) T cell precursors by 4 weeks. By 6 weeks, 30-40% of ATO cells were CD3+TCRαβ+ T cells, of which 20-30% were mature CD8 single positive (SP) T cells. CD4SP cells were generated at a lower frequency and later in culture (2-14% of CD3+TCRαβ+ cells). ATO-derived T cells exhibited a naïve CD45RA+CD27+CCR7+CD62L+ phenotype, a diverse, thymic-like TCR repertoire, and robust TCR-dependent cytokine release and proliferation. Transduction of CB CD34+ HSPCs with an HLA-A*02:01-restricted αβ TCR specific for NY-ESO-1 resulted in a markedly increased cell output per ATO (>400-fold, relative to input HSPCs) and enhanced generation of naïve CD3+TCRαβ+CD8αβ+ conventional T cells, the majority of which were antigen-specific by tetramer staining. Positive selection of TCR-engineered naïve T cells could be further enhanced by expression of cognate HLA-A*02:01 in ATO stromal cells. ATO-derived TCR-engineered T cells exhibited a near complete lack of endogenous TCR Vβ expression, consistent with induction of allelic exclusion by the exogenous TCR during T cell development. ATO-derived engineered T cells underwent antigen-specific cytotoxic priming, polyfunctional cytokine release, and proliferation in response to artificial APCs; and exhibited antigen-specific killing of NY-ESO-1+ tumor cells in vitro and in vivo. ATOs thus present a highly efficient off-the-shelf platform for the generation of clinically relevant numbers of naïve and potentially non-alloreactive engineered T cells for adoptive immunotherapy. Clinical translation of the ATO system will be aided by its simplicity, scalability, use of serum-free components, and compatibility with irradiated stromal cells. In addition, genetic manipulation of stem or stromal cell components can be easily incorporated into the system to further enhance downstream T cell engraftment or function. Disclosures Seet: Kite Pharma: Patents & Royalties: Kite Pharma holds an exclusive license to certain intellectual property. Montel-Hagen:Kite Pharma: Patents & Royalties: Kite Pharma holds an exclusive license to certain intellectual property. Crooks:Kite Pharma: Patents & Royalties: Kite Pharma holds an exclusive license to certain intellectual property, Research Funding.

scholarly journals A voltage-gated sodium channel is essential for the positive selection of CD4+ T cells

2012 ◽  
Vol 13 (9) ◽  
pp. 880-887 ◽  
Author(s):  
Wan-Lin Lo ◽  
David L Donermeyer ◽  
Paul M Allen
Keyword(s):  
T Cells ◽  
Sodium Channel ◽  
Positive Selection ◽  
Cd4 T Cells ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Selection Of

scholarly journals Positive selection determines T cell receptor V beta 14 gene usage by CD8+ T cells.

1989 ◽  
Vol 170 (1) ◽  
pp. 135-143 ◽  
Author(s):  
N S Liao ◽  
J Maltzman ◽  
D H Raulet
Keyword(s):  
T Cells ◽  
T Cell ◽  
Positive Selection ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Radiation Chimeras ◽  
Gene Usage ◽  
Selection Of

We report here a mAb, 14-2, reactive with TCRs that include V beta 14. The frequency of V beta 14+ T cells varies with CD4 and CD8 subset and is controlled by the H-2 genes. Thus CD8+ T cells from H-2b mice include approximately 2.3% V beta 14+ T cells while CD8+ T cells from mice expressing K kappa include greater than 8% V beta 14+ T cells. In all strains examined, 7-8% of CD4+ T cells express V beta 14. The frequent usage of V beta 14 in CD8+ T cells of K kappa-expressing mice is a result of preferential positive selection of V beta 14+ CD8+ T cells as demonstrated by analysis of radiation chimeras. These studies demonstrate that H-2-dependent positive selection occurs in unmanipulated mice. Furthermore, the results imply that positive selection, and possibly H-2 restriction, can be strongly influenced by a V beta domain, with some independence from the beta-junctional sequence and alpha chain.

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