scholarly journals Generation of diversity in T cell receptor repertoire specific for pigeon cytochrome c.

1987 ◽  
Vol 165 (2) ◽  
pp. 279-301 ◽  
Author(s):  
S B Sorger ◽  
S M Hedrick ◽  
P J Fink ◽  
M A Bookman ◽  
L A Matis
Keyword(s):  
T Cell ◽  
Cytochrome C ◽  
T Cell Receptor ◽  
Cell Lines ◽  
Dna Sequences ◽  
Cell Receptor ◽  
T Cell Response ◽  
Beta Chain ◽  
Antigen Specificity ◽  
T Cell Lines

17 T cell clones and 3 T cell lines, specific for pigeon cytochrome c, were analyzed for fine specificity and rearranged T cell receptor (TCR) gene elements. Clones of similar fine specificities were grouped into one of four phenotypes, and correlations between phenotype differences and gene usage could be made. All the lines and clones rearranged a member of the V alpha 2B4 gene family to a limited number of J alpha regions. The beta chain was made up of one of three non-cross-hybridizing V beta regions, each rearranging to only one or two J beta s. The use of alternate V beta regions could be correlated with phenotype differences, which were manifested either as MHC- or MHC and antigen-specificity changes. In addition, the presence of alloreactivity, which defined a phenotype difference, could be correlated solely with the use of an alternate J alpha region. These observations were substantiated by prospective analyses of pigeon cytochrome c-specific T cell lines that were selected for alternate MHC specificity or alloreactivity and were found to express the correlated alpha and beta chain rearrangements. Previously, the TCR DNA sequences from two clones, each representing a variant of one phenotype, showed sequence differences only in the N regions of their TCR genes. Since only these two variants, using identical V alpha-J alpha and V beta-J beta gene elements, were repeatedly observed in this study, we would predict that the junctional diversity differences are selectable. In this T cell response, all the gene elements involved in the generation of diversity appear to be selected, and may therefore be important in the determination of TCR specificity. This high degree of receptor gene selection represents a fundamental difference from the diversity seen in several extensively analyzed antibody responses.

scholarly journals T cell receptor (TCR) beta chain homodimers on the surface of immature but not mature alpha, gamma, delta chain deficient T cell lines.

1992 ◽  
Vol 11 (7) ◽  
pp. 2735-2745 ◽  
Author(s):  
M. Groettrup ◽  
A. Baron ◽  
G. Griffiths ◽  
R. Palacios ◽  
H. von Boehmer
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Lines ◽  
Cell Receptor ◽  
Beta Chain ◽  
Gamma Delta ◽  
T Cell Lines

Analysis of Function, Specificity and T Cell Receptor Expression of Cloned Mucosal T Cell Lines in Crohn's Disease

1996 ◽  
Vol 9 (2) ◽  
pp. 193-204 ◽  
Author(s):  
Thomas P. Prindiville ◽  
Mary C. Cantrell ◽  
Takayuki Matsumoto ◽  
William R. Brown ◽  
Aftab A. Ansari ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
T Cell ◽  
Crohn's Disease ◽  
T Cell Receptor ◽  
Cell Lines ◽  
Cell Receptor ◽  
Receptor Expression ◽  
T Cell Lines ◽  
Analysis Of Function

scholarly journals Configuration and expression of the T cell receptor beta chain gene in human T-lymphotrophic virus I-infected cells.

1986 ◽  
Vol 163 (2) ◽  
pp. 383-399 ◽  
Author(s):  
R F Jarrett ◽  
H Mitsuya ◽  
D L Mann ◽  
J Cossman ◽  
S Broder ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Function ◽  
Tumor Cells ◽  
T Cell Receptor ◽  
Cell Lines ◽  
Primary Tumor ◽  
Gene Rearrangement ◽  
Cell Receptor ◽  
Beta Chain ◽  
Beta Gene

We studied the configuration and expression of the gene encoding the beta chain of the T cell receptor (TCR beta) in cell lines and primary tumor cells infected by the human T cell leukemia/lymphoma (lymphotrophic) virus type I (HTLV-I). Most of the cell lines and all the primary tumor cells showed rearrangement of the TCR beta gene, and in each case the rearrangement was distinct. The majority of cases examined were clonal with respect to a particular TCR beta gene rearrangement. Primary tumor cells from one case (SD) were found to have a tandem duplication of a portion of chromosome 7; this appears to have resulted in the presence of three alleles of the TCR beta gene, each of which is arranged differently. This suggests that the chromosomal abnormality, and possibly infection by HTLV-I, occurred before TCR beta gene rearrangement. Cell lines infected by HTLV-I express levels of TCR beta mRNA similar to PHA stimulated lymphocytes, suggesting that this gene is not transcriptionally activated as a result of infection by HTLV-I. Cloned T cells of known antigen specificity that are infected by HTLV-I in vitro show impairment of immune function, including loss of antigen-specific responsiveness and the acquisition of alloreactivity. Comparison of the configuration of the TCR beta gene before and after infection revealed no changes detectable by Southern blot analysis. Levels of expression of the TCR beta gene at the mRNA level and surface expression of the T3 complex were also not significantly altered, suggesting that changes in immune function cannot be attributed to quantitative changes in the TCR molecule. The configuration of the TCR beta gene in primary tumor cells infected by HTLV-I was compared with that in the derived cell lines. In all pairs examined, the configuration in the primary tumor cells was different from that in the cell lines, strongly suggesting that the cells that grow in culture are not the original neoplastic cells.

In Vivo Generation of Oligoclonal Colitic CD4+ T-Cell Lines Expressing a Distinct T-Cell Receptor Vβ

2005 ◽  
Vol 128 (5) ◽  
pp. 1268-1277 ◽  
Author(s):  
Ana C. Abadía-Molina ◽  
Atsushi Mizoguchi ◽  
William A. Faubion ◽  
Ype P. de Jong ◽  
Svend T. Rietdijk ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Lines ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
T Cell Lines ◽  
T Cell Receptor Vβ

Establishment of T-cell Lines from Infiltrated NOD Islets by Stimulation of Specific T-Cell Receptor Vβ Segments

1993 ◽  
Vol 6 (4) ◽  
pp. 423-436 ◽  
Author(s):  
Didier Maugendre ◽  
Béatrice Legrand ◽  
Martine Olivi ◽  
Pierre Bedossa ◽  
Jean-François Bach ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Lines ◽  
Cell Receptor ◽  
T Cell Lines ◽  
T Cell Receptor Vβ ◽  
Stimulation Of

Recombination of Endogenous TCR Chains with Retrovirally Introduced TCR Chains Can Result in Mixed T Cell Receptor Dimers Harbouring Harmful Alloreactivity

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 823-823
Author(s):  
Marleen M Van Loenen ◽  
Renate de Boer ◽  
Gerdien L Volbeda ◽  
Avital L Amir ◽  
Renate S. Hagedoorn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Gene Transfer ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Beta Chain ◽  
Antigen Specificity ◽  
Alpha Chain ◽  
Cell Clones ◽  
Engineered T Cells

Abstract T cell receptor transfer to engineer tumor specific T cells is being explored as a strategy for adoptive immunotherapy. By retroviral introduction of T cell receptors (TCRs), large numbers of T cells with defined antigen specificity can be obtained. The in vivo efficacy of adoptively transferred TCR engineered T cells has been demonstrated in mouse studies and recently the first clinical trial with TCR engineered T cells was performed in melanoma patients. However, a potential drawback of TCR gene transfer is the formation of mixed TCR dimers. Chains of the introduced TCR can pair with the endogenous TCR chains, resulting in unknown specificities, and potentially in harmful reactivity against patient HLA molecules. We investigated whether TCR gene transfer leads to the generation of new detrimental reactivities by creating T cells that expressed mixed TCR dimers. To be able to discriminate between the antigen specificity of the mixed TCR dimers and the introduced as well as the endogenous TCR, we transduced mono-specific T cells with seven different antigen specific TCRs. As mono-specific T cells we used CMV-pp50 specific HLA-A1 restricted T cells. The transduced T cells were analyzed for newly acquired specificities against a large HLA-typed EBV-LCL panel covering almost all HLA class I and II molecules. We transduced several polyclonal virus specific T cell populations with the seven different antigen specific TCRs, and showed that in all T cell populations at least one of the seven TCR-transduced populations acquired new alloreactivities. Furthermore, by randomly combining TCR alpha and beta chains derived from different T cell clones we created 60 mixed TCR dimers of which 17 acquired alloreactivity. These results indicate that recombination of the introduced TCR chains with the endogenous TCR chains frequently gives rise to new allospecificities. To ascertain that the newly acquired alloreactivities were exerted by mixed TCR dimers, we introduced only TCR alpha or beta chains into CMV-pp50 specific monoclonal T cells, and demonstrated for example, that the introduction of a CMV pp65 specific TCR alpha chain led to a newly acquired reactivity that was HLA B58 restricted. The introduction of only the beta chain of a minor histocompatibility antigen (mHag) HA-1 specific TCR led to a newly acquired HLA B52 specific reactivity. Furthermore, we analyzed whether mixed TCR dimers consisting of conserved TCRs with the same specificity could acquire new harmful reactivity. We recombined mHag HA-2 specific TCR alpha and beta chains from 4 different T cell clones. Of the 12 mixed TCR dimers, a combination of the mHag HA-2 specific TCR alpha chain derived from the HA2.6 T cell clone with the mHag HA-2 specific beta chain of clone HA2.19 resulted in alloreactivity that was HLA DQ3 restricted. These results indicate that each recombination of TCR chains after TCR gene transfer can potentially result in a harmful new reactivity. In conclusion, mixed TCR dimers due to pairing of endogenous TCR chains with introduced TCR chains acquire potentially dangerous reactivities, both class I and class II restricted. To limit the chance of generating self- or alloreactive T cells, TCRs may be constructed allowing selective pairing of the TCR alpha chain with the corresponding TCR beta chain. Alternatively, we propose to use virus specific T cells as host cells for TCR gene transfer. Since they consist of a restricted TCR repertoire, the number of different chimeric TCRs formed will be limited. By introducing into these T cells as controls only the alpha or beta chain of the TCR of interest, the reactivity of these T cells and harmful reactivities of the mixed TCR dimers can be tested against different patient derived cell types.

scholarly journals Reconstitution of T cell receptor signaling in ZAP-70-deficient cells by retroviral transduction of the ZAP-70 gene.

1996 ◽  
Vol 184 (5) ◽  
pp. 2031-2036 ◽  
Author(s):  
N Taylor ◽  
K B Bacon ◽  
S Smith ◽  
T Jahn ◽  
T A Kadlecek ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Lines ◽  
Leukemia Virus ◽  
Severe Combined Immunodeficiency ◽  
Cell Receptor ◽  
Type I ◽  
Tcr Signaling ◽  
Cell Leukemia Virus Type ◽  
T Cell Lines

A variant of severe combined immunodeficiency syndrome (SCID) with a selective inability to produce CD8 single positive T cells and a signal transduction defect in peripheral CD4+ cells has recently been shown to be the result of mutations in the ZAP-70 gene. T cell receptor (TCR) signaling requires the association of the ZAP-70 protein tyrosine kinase with the TCR complex. Human T cell leukemia virus type I-transformed CD4+ T cell lines were established from ZAP-70-deficient patients and normal controls. ZAP-70 was expressed and appropriately phosphorylated in normal T cell lines after TCR engagement, but was not detected in T cell lines from ZAP-70-deficient patients. To determine whether signaling could be reconstituted, wild-type ZAP-70 was introduced into deficient cells with a ZAP-70 retroviral vector. High titer producer clones expressing ZAP-70 were generated in the Gibbon ape leukemia virus packaging line PG13. After transduction, ZAP-70 was detected at levels equivalent to those observed in normal cells, and was appropriately phosphorylated on tyrosine after receptor engagement. The kinase activity of ZAP-70 in the reconstituted cells was also appropriately upregulated by receptor aggregation. Moreover, normal and transduced cells, but not ZAP-70-deficient cells, were able to mobilize calcium after receptor ligation, indicating that proximal TCR signaling was reconstituted. These results indicate that this form of SCID may be corrected by gene therapy.

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