Reconstitution of MHC class I specificity by transfer of the T cell receptor and Lyt-2 genes

Gabert, Jean; Langlet, Claire; Zamoyska, Rose; Parnes, Jane R.; Schmitt-Verhulst, Anne-Marie; Malissen, Bernard

doi:10.1016/0092-8674(87)90027-4

Cited by 209 publications

(89 citation statements)

References 51 publications

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“…The specific reactivity of a T cell for a particular antigen and self-MHC is determined by the TCR; transfection of rearranged TCR genes from a T-cell clone reactive for a particular antigen and self-MHC pair will render the recipient responsive to this antigen and MHC complex (23,24). An efficient response to antigen and MHC also requires the presence of CD4 or CD8 (25)(26)(27)(28). The relative contribution of the TCR and CD4 or CD8 to the specificity for allogeneic class I or class II is not clear.…”

Section: Methodsmentioning

confidence: 99%

Expression of CD4 in transgenic mice alters the specificity of CD8 cells for allogeneic major histocompatibility complex.

Robey

Ramsdell²,

Elliott³

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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We have generated a transgenic mouse line in which a CD4 transgene is expressed on a significant fraction of the mature CD8' lymphocytes but is not expressed in the thymus. This provides an opportunity to examine the func- (5)(6)(7)(8). However, for assays in which T cells are required to produce lymphokines and initiate a response to foreign MHC, the correlation between CD4/CD8 phenotype and MHC class specificity is absolute (5, 9, 10).There are two molecules on class II-specific T cells that recognize class II MHC: TCR and CD4. It is unclear which of these molecules is responsible for the specificity for foreign class II MHC. We have investigated this question by using a line of mice in which a CD4 transgene is expressed on a subset of mature CD8' cells but is not expressed in the thymus. We find that mature CD8' cells that express the CD4 transgene proliferate both to class I and class II allogeneic MHC. This suggests that the presence of CD4 or CD8, rather than the specificity of the TCR, determines whether a population of cells will respond to foreign class I or class II MHC.

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Section: Methodsmentioning

confidence: 99%

Expression of CD4 in transgenic mice alters the specificity of CD8 cells for allogeneic major histocompatibility complex.

Robey

Ramsdell²,

Elliott³

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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“…Transfections of T1.4 hybridomas with protoplasts and selection in the presence of G418 were performed as described (36) to generate the T1.4.1 ␣␤, T1.4.1 ␣Ј␤, and T1.4.1 ␣Љ␤ cell lines. Alternatively, a clone that lost CD8␤ surface expression was obtained (T1.4.2 ␣␣) from T1.4 hybridoma transfected with CD8␣.…”

Section: Transfection and Infectionmentioning

confidence: 99%

Essential Role of CD8 Palmitoylation in CD8 Coreceptor Function

Arcaro

Grégoire

Boucheron

et al. 2000

The Journal of Immunology

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159

164

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To investigate the molecular basis that makes heterodimeric CD8αβ a more efficient coreceptor than homodimeric CD8αα, we used various CD8 transfectants of T1.4 T cell hybridomas, which are specific for H-2Kd, and a photoreactive derivative of the Plasmodium berghei circumsporozoite peptide PbCS 252–260 (SYIPSAEKI). We demonstrate that CD8 is palmitoylated at the cytoplasmic tail of CD8β and that this allows partitioning of CD8αβ, but not of CD8αα, in lipid rafts. Localization of CD8 in rafts is crucial for its coreceptor function. First, association of CD8 with the src kinase p56lck takes place nearly exclusively in rafts, mainly due to increased concentration of both components in this compartment. Deletion of the cytoplasmic domain of CD8β abrogated localization of CD8 in rafts and association with p56lck. Second, CD8-mediated cross-linking of p56lck by multimeric Kd-peptide complexes or by anti-CD8 Ab results in p56lck activation in rafts, from which the abundant phosphatase CD45 is excluded. Third, CD8-associated activated p56lck phosphorylates CD3ζ in rafts and hence induces TCR signaling and T cell activation. This study shows that palmitoylation of CD8β is required for efficient CD8 coreceptor function, mainly because it dramatically increases CD8 association with p56lck and CD8-mediated activation of p56lck in lipid rafts.

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“…An alternative approach to obtain large numbers of T cells with the desired specificities is the transfer of TCRa and TCRb chain genes into patient T cells. It was shown already some time ago that antigen specificity can be transferred by TCR gene transfer into mouse T cells [5,6]. Only recently has it been recognized that TCR gene transfer into primary T cells is a useful strategy to construct antigen-specific T cells for therapy.…”

Section: Introductionmentioning

confidence: 99%

Designer T cells by T cell receptor replacement

et al. 2006

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T cell receptor (TCR) gene transfer is a convenient method to produce antigen-specific T cells for adoptive therapy. However, the expression of two TCR in T cells could impair their function or cause unwanted effects by mixed TCR heterodimers. With five different TCR and four different T cells, either mouse or human, we show that some TCR are strong -in terms of cell surface expression -and replace weak TCR on the cell surface, resulting in exchange of antigen specificity. Two strong TCR are co-expressed. A mouse TCR replaces human TCR on human T cells. Even though it is still poorly understood why some TCRa/b combinations are preferentially expressed on T cells, our data suggest that, in the future, designer T cells with exclusive tumor reactivity can be generated by T cell engineering.

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Reconstitution of MHC class I specificity by transfer of the T cell receptor and Lyt-2 genes

Cited by 209 publications

References 51 publications

Expression of CD4 in transgenic mice alters the specificity of CD8 cells for allogeneic major histocompatibility complex.

Expression of CD4 in transgenic mice alters the specificity of CD8 cells for allogeneic major histocompatibility complex.

Essential Role of CD8 Palmitoylation in CD8 Coreceptor Function

Designer T cells by T cell receptor replacement

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