A T cell clone expresses two T cell receptor α genes but uses one αβ heterodimer for allorecognition and self MHC-restricted antigen recognition

Malissen, Marie; Trucy, Jeannine; Letourneur, François; Rebaï, Najet; Dunn, Daniel E.; Fitch, F W; Hood, Leroy; Malissen, Bernard

doi:10.1016/0092-8674(88)90008-6

Cited by 184 publications

(99 citation statements)

References 49 publications

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“…At that point, the ␤-chains would become limiting, and only the ␣-chain with the higher affinity for pairing to the ␤-chain would be expressed on the cell surface (10). This type of competition has been suggested previously for mature T cells (7,43). Therefore, we used two different methods to test this.…”

Section: Discussionmentioning

confidence: 99%

Allelic Exclusion of the TCR α-Chain Is an Active Process Requiring TCR-Mediated Signaling and c-Cbl

Niederberger

Holmberg

Alam

et al. 2003

The Journal of Immunology

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Phenotypic allelic exclusion at the TCRα locus is developmentally regulated in thymocytes. Many immature thymocytes express two cell surface α-chain species. Following positive selection, the vast majority of mature thymocytes and peripheral T cells display a single cell surface α-chain. A posttranslational mechanism occurring at the same time as positive selection and TCR up-regulation leads to this phenotypic allelic exclusion. Different models have been proposed to explain the posttranslational regulation of the α-chain allelic exclusion. In this study, we report that allelic exclusion is not regulated by competition between distinct α-chains for a single β-chain, as proposed by the dueling α-chain model, nor by limiting CD3 ζ-chain in mature TCRhigh thymocytes. Our data instead favor the selective retention model where the positive selection signal through the TCR leads to phenotypic allelic exclusion by specifically maintaining cell surface expression of the selected α-chain while the nonselected α-chain is internalized. The use of inhibitors specific for Lck and/or other Src kinases indicates a role for these protein tyrosine kinases in the signaling events leading to the down-regulation of the nonselectable α-chain. Loss of the ubiquitin ligase/TCR signaling adapter molecule c-Cbl, which is important in TCR down-modulation and is a negative regulator of T cell signaling, leads to increased dual α-chain expression on the cell surface of double-positive thymocytes. Thus, not only is there an important role for TCR signaling in causing α-chain allelic exclusion, but differential ubiquitination by c-Cbl may be an important factor in causing only the nonselected α-chain to be down-modulated.

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Section: Discussionmentioning

confidence: 99%

Allelic Exclusion of the TCR α-Chain Is an Active Process Requiring TCR-Mediated Signaling and c-Cbl

Niederberger

Holmberg

Alam

et al. 2003

The Journal of Immunology

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“…The accumulation of TCR␤ low DP thymocytes in TCR␣ sJ/sJ mice may also reflect the diminished capacity of these cells to generate a productive VJ␣ rearrangement that encodes a TCR␣ chain capable of pairing with the specific TCR␤ chain (33)(34)(35). Thus, TCR␣ chain gene revision may be important at the TCR␤ low to TCR␤ int DP thymocyte checkpoint to optimize for the generation of a VJ␣ rearrangement that both is productive and encodes a TCR␣ chain capable of pairing with the TCR␤ chain to generate an ␣␤ TCR.…”

Section: Discussionmentioning

confidence: 99%

Revision of T cell receptor α chain genes is required for normal T lymphocyte development

Huang

Sleckman

Kanagawa

2005

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

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To become mature ␣␤ T cells, developing thymocytes must first assemble a T cell receptor (TCR) ␤ chain gene encoding a TCR␤ chain that forms a pre-TCR. These cells then need to generate a TCR␣ chain gene encoding a TCR␣ chain, which, when paired with the TCR␤ chain, forms a selectable ␣␤ TCR. Newly generated VJ␣ rearrangements that do not encode TCR␣ chains capable of forming selectable ␣␤ TCRs can be excised from the chromosome and replaced with new VJ␣ rearrangements. Such replacement occurs through the process of TCR␣ chain gene revision whereby a V␣ gene segment upstream of the VJ␣ rearrangement is appended to a downstream J␣ gene segment. A multistep, gene-targeting approach was used to generate a modified TCR␣ locus (TCR␣ sJ ) with a limited capacity to undergo revision of TCR␣ chain genes. Thymocytes from mice homozygous for the TCR␣ sJ allele are defective in their ability to generate an ␣␤ TCR. Furthermore, those thymocytes that do generate an ␣␤ TCR have a diminished capacity to be positively selected, and TCR␣ sJ/sJ mice have significantly reduced numbers of mature ␣␤ T cells. Together, these findings demonstrate that normal T cell development relies on the ability of developing thymocytes to revise their TCR␣ chain genes.T he checkpoints imposed on developing T cells mandate that they generate T cell receptor (TCR) ␣ and ␤ chains that form an ␣␤ TCR capable of positive selection (1). TCR ␣ and ␤ chain gene assembly is precisely regulated within the context of normal thymocyte development. TCR␤ chain genes are assembled in CD4 Ϫ ͞CD8 Ϫ [double negative (DN)] thymocytes (2-4). Expression of a TCR␤ chain, as a pre-TCR, results in signals that promote cellular expansion and developmental stage progression to the CD4 ϩ ͞CD8 ϩ [double positive (DP)] stage of thymocyte development (5). Pre-TCR signals also promote TCR␣ chain gene assembly and prohibit further TCR␤ chain gene assembly through the process of allelic exclusion (5-7). Because allelic exclusion prohibits DP thymocytes from generating new TCR␤ chains, these cells must generate TCR␣ chains that form an ␣␤ TCR capable of positive selection if they are to become mature T cells.The genes encoding the TCR␣ chain are intermingled with TCR␦ chain genes in the TCR␣͞␦ locus ( Fig. 1) (8). TCR␣ variable region genes are assembled from V␣ and J␣ gene segments. There are Ϸ100 V␣ gene segments clustered in the 5Ј region of the mouse TCR␣͞␦ locus and 61 J␣ gene segments, spanning Ϸ60 kb, clustered in the 3Ј region of the locus (Fig. 1) (8). The V␣ and J␣ gene segments are oriented such that any rearrangement occurs by deletion, excising the intervening DNA from the chromosome (8).Thymocytes entering the DP compartment from the DN compartment express low TCR␤ chain levels, as the pre-TCR, and are referred to as TCR␤ low DP thymocytes. Initial V␣ rearrangements in these cells are targeted to the most 5Ј J␣ gene segments through the activity of the T early ␣ (TEA) promoter (9). A nonproductive VJ␣ rearrangement could be followed by a VJ␣ rearrangement on the oth...

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“…Transfer to nitrocellulose and hybridizalion proeedures were per· formed as previously deseribed (Malissen et al, 1988).…”

Section: Rna Pcr Ampllflcatlonmentioning

confidence: 99%

The T cell receptor/CD3 complex is composed of at least two autonomous transduction modules

Wegener

Letourneur

Hoeveler

et al. 1992

Cell

Self Cite

415

294

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SummaryReeent studies have demonstrated that the CD3-~ subunlt of the T eell antigen reeeptor (TCR) eomplex Is involved In signal transduetlon. However, the funetlon of the remalnlng Invariant subunits, CD3-y, -ö, and e, Is still poorly understood. To examine thelr role In TCR funetlon, we have eonstrueted TCR/CD3 eomplexes devold of tunetlonal ~ subunlt and showed that they are still able to trigger the produellon of Interleukln-2 in response to antigen or superantigen. These data, together with previous results, Indleate that the TCR/ CD3 eomplex Is eomposed of at least two parallel Iransduelng unlts, made 01 the YÖE and ~ ehalns, respeetlvely, Furthermore, the analysis 01 partially truneated ~ ehains has led us to Indlvlduallze a lunetlonal domaln that may have eonstltuted the buildlng block of most of the transduelng subunlts assoelated wlth antigen reeeptors and some Fe receptors. IntroduetionThe T cell antigen receptor (TCR) is a multisubunit complex composed of the products of at least six distinct genes. The TCR a and TCR ß subunits exist as disulfidelinked heterodimers, possess short cytoplasmic tails, and contain clonally variable regions that determine the antigenic specificity of the complex. The remaining subunits, termed CD3-y, -ö, -E, -~, and -1], are invariant, noncovalently associated with the TCR aß dimer, and possess large intracytoplasmic domains thought to be responsible for coupling antigen recognition to various signal transductlon pathways. The evolutionarily related y, Ö, and e subunits are expressed as noncovalently associated ye and OE pairs (Koning et al., 1990;Blumberg et al. , 1990; De la Herra et al. , 1991), and display immunoglobulin-like extracellular domains (Gold et al., 1987). In contrast, the ~ and 1] subunlts contaln an extracellular domain of only 9 residues and constitute the prototype of a new protein family that includes the y chain of the high affinity IgE receptor (FceRI)

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A T cell clone expresses two T cell receptor α genes but uses one αβ heterodimer for allorecognition and self MHC-restricted antigen recognition

Cited by 184 publications

References 49 publications

Allelic Exclusion of the TCR α-Chain Is an Active Process Requiring TCR-Mediated Signaling and c-Cbl

Allelic Exclusion of the TCR α-Chain Is an Active Process Requiring TCR-Mediated Signaling and c-Cbl

Revision of T cell receptor α chain genes is required for normal T lymphocyte development

The T cell receptor/CD3 complex is composed of at least two autonomous transduction modules

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