Participation of CD4 coreceptor molecules in T-cell repertoire selection

Teh, Hung‐Sia; Garvin, Alex M.; Forbush, Katherine A.; Carlow, Douglas A.; Davis, Craig B.; Littman, Dan R.; Perlmutter, Roger M.

doi:10.1038/349241a0

Cited by 80 publications

(44 citation statements)

References 24 publications

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“…This suggests that although CDS-independent CTL with high-affinity reeeptors for antigen ean funetion in the periphery, their generation is dependent on this eo-reeeptor during ontogeny. This requirement eould refleet the aetion of CDS as an aeeessory moleeule with low-density class I on thymie stromal eells where edueation oeeurs, but we favour CDS as a eo-reeeptor required for signalling 20 • The finding that anti-L d alloreaetive T eells are not eompletely eliminated in L Q3 animals eould refleet either the retention of low-affinity eells requiring CDS as an aeeessory moleeule, or a CDS-dependent eo-reeeptor signalling event required for effieient negative seleetion. 0…”

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confidence: 85%

Negative and positive selection of antigen-specific cytotoxic T lymphocytes affected by the α3 domain of MHC I molecules

Aldrich

Hammer

Jones-Youngblood

et al. 1991

Nature

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As with studies on the Na + / K + pump24, early results on Na+ /Ca 2 + exchange appeared inconsistent with consecutive ion exchange models (see ref. 5 for review). Our work provides strong support for a consecutive Na +/Ca2+ exchange mechanism a nd should facilitate structure-function studies ofthe cloned Na+ /Ca2+ exchanger. The results of both ion jump experiments and steady-state I ~aCa measurements are inconsistent with Ca2+ translocation involving net negative cha rge movement 8• We conclude from our site-density estimates and I NaCa measurements that max imum exchanger turnover rates are about 5,000 S -I . As alread y proposed for the Na + / K + pumpl 2-17 and rod out er segment Na + / Ca2+ , K + excha nger 2 ,22, voltage-dependence must reside in the binding and release of extracellular Na+ or a closely associated occlusion/ deocclusion reaction. THE al and a2 domains of major histocompatibility complex (MHC) class I molecules function in the binding and presentation of foreign peptides to the T-cell antigen receptor and control both negative and positive selection of the T-ce)) repertoire l -3 , Although the a3 domain of class I is not involved in peptide binding, it does interact with the T-cell accessory molecule, CD8 (refs 4, 5). CD8 is important in the selection of T cells as anti-CD8 antibody injected into perinatal mice interfers with this process 6 • We previously used a hybrid class I molecule with the a 11 a2 domains from L d and the a3 domain from Q7 b and showed that this molecule 718 binds an Ld-restricted peptide but does not interact with CD8-dependent cytotoxic T lymphocytes 7• Expression of this molecule in transgenic mice faUs to negatively select a subpopulation of anti-L d cytotoxic T Iymphocytes. In addition, positive selection of virus-specific L d -restricted cytotoxic T lymphocytes does not occur. We conclude that besides the a1la2 domains of class I, the a3 domain plays an important part in both positive and negative selection of antigen-specific cells.To examine the role of the a3 domain of class I molecules in the responses of alloreactive and antigen-specific cytotoxic T Iymphocytes (CTL), we generated two transgenic mouse strains, C3H.L d and C3H.L Q 3, derived from C3H/ HeJ (H_2 k ) mi ce. C3H .L d express inta ct L d , whereas C3H.LQ3 ex press a n LU molecule whose a3 domain is switched with Q7 b . The Q7 b a 3 domain differs from LU at live residues and in addition has a unique three-amino-acid insert at positions 275-277 (ref. 8). We showed that this molecule (L Q3) binds the same viral peptide as L d but is not recognized by peptide-specific CD8-dependent CTL (ref. 7). Similar observations have been reported with a 3 mutant class I molecules not recognized by CD8-dependent CTL, the defect being due to an alteration in the binding site for C D8 (refs 4,5). 80th L d and L Q3 genes contain the same Qj .0

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confidence: 85%

Negative and positive selection of antigen-specific cytotoxic T lymphocytes affected by the α3 domain of MHC I molecules

Aldrich

Hammer

Jones-Youngblood

et al. 1991

Nature

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“…Recent studies suggest that CD4, through its interaction with MHC class II molecules expressed in the thymic microenvironment, also has a critical function in the selection of the T-cell repertoire during thymic ontogeny (7,25,33,38). In this process, CD4-CD8-pre-T cells differentiate into either CD4+ CD8-or CD4-CD8+ T cells through an intermediate CD4+ CD8+ stage.…”

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Identification and characterization of a T-cell-specific enhancer adjacent to the murine CD4 gene.

Sawada¹,

Littman²

1991

Mol. Cell. Biol.

115

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Expression of the CD4 and CD8 glycoproteins is a tightly regulated process tied to the maturation of functionally distinct classes of thymocytes. Therefore, understanding of the mechanism of expression of the genes encoding CD4 and CD8 is likely to yield important insight into regulation of the differentiated functions of T cells. Here, we report the identification of a T-cell-specific enhancer in a DNase I-hypersensitive region about 13 kb 5' of the transcription initiation site of the murine CD4 gene. Within the minimal enhancer element, at least three nuclear protein binding sites were identified by DNase I footprint analysis. One site contains the consensus motif for TCF-loLEF-1, a recently identified HMG box transcription factor primarily expressed in.pre-B and T cells. By Southwestern (DNA-protein) blotting and binding competition analyses, the protein binding to this site was found to be indistinguishable from TCF-la/LEF-1. Mutagenesis of this site resulted in loss of factor binding but had a relatively minor effect on enhancer activity. In contrast, mutations in another site, containing two consensus binding motifs for basic helix-loop-helix proteins, abolished factor binding and dramatically reduced enhancer activity. None of the protein binding sites had activity on its own, suggesting that the CD4 enhancer requires the interaction of multiple regulatory sites.The T-cell surface glycoprotein CD4 is expressed on helper T cells and plays an important signaling role during antigen recognition by binding to a nonpolymorphic region of major histocompatibility complex (MHC) class II molecules (5, 9, 23, 31). Recent studies suggest that CD4, through its interaction with MHC class II molecules expressed in the thymic microenvironment, also has a critical function in the selection of the T-cell repertoire during thymic ontogeny (7,25,33,38). In this process, CD4-CD8-pre-T cells differentiate into either CD4+ CD8-or CD4-CD8+ T cells through an intermediate CD4+ CD8+ stage. It is therefore thought that expression of the genes encoding both CD4 and CD8 glycoproteins is positively regulated during the transition from the CD4-CD8-stage to the double-positive stage and then negatively regulated in a mutually exclusive manner during the transition to the single-positive stage. The down-regulation of either CD4 or CD8 gene expression appears to be closely coordinated with the positive selection of T cells bearing appropriate T-cell receptors (TCRs) such that T cells bearing TCRs which recognize MHC class II molecules retain expression of CD4 but shut off CD8, while cells with MHC class I-specific TCRs retain expression of CD8 but shut off CD4 (reviewed in reference 6). The mechanisms governing expression of the CD4 and CD8 genes during these developmental processes remain poorly understood.Previous studies on T-cell-specific gene expression have focused on genes that are expressed in all mature T lymphocytes, such as genes encoding components of the TCR complex (3,16,20 accompanied by their differentiation into helper ...

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“…that CD4 overexpression, without concomitant increases in associated p56lck (lck) tyrosine kinase molecules, might paradoxically interfere with CD4 signaling and so might affect TCR expression in immature CD4+CD8+ thymocytes. To do so, we utilized CD4 transgenic (CD4-Tg) mice expressing a CD4 transgene controlled by the lck proximal promoter (line 727) and that markedly overexpresses CD4 (6). Indeed, the present study reveals that the signaling competence of a surface receptor can be significantly diminished when its expression is disproportionate to that of its associated cytoplasmic signaling molecule.…”

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Decreased signaling competence as a result of receptor overexpression: overexpression of CD4 reduces its ability to activate p56lck tyrosine kinase and to regulate T-cell antigen receptor expression in immature CD4+CD8+ thymocytes.

Nakayama

Wiest

Abraham

et al. 1993

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

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Thymic selection of the developing T-celi repertoire occurs in immature CD4+CD8+ thymocytes, with the fate of individual thymocytes determined by the specificity of T-celi antigen receptor they express. However, T-cell antigen receptor expression in immature CD4+CD8+ thymocytes is actively down-regulated in CD4+CD8+ thymocytes by CD4-mediated tyrosine kinase signals that are generated in the thymus as a result of CD4 engagement by intrathymic ligands. In the present study we In fact, TCR expression in CD4+CD8+ thymocytes has been shown to be actively down-regulated by CD4-mediated signals that are generated as a result of CD4 engagement in the thymus (2)(3)(4). We have recently demonstrated that regulation of TCR expression by such CD4 signals in CD4+CD8+ thymocytes is mediated by activation of associated tyrosine kinase molecules (5).The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.Consequently, we were interested in assessing the effect of CD4 overexpression on CD4 signaling and TCR expression in immature CD4+CD8+ thymocytes. We specifically wished to assess the premise suggested by one of us (R.M.P.) that CD4 overexpression, without concomitant increases in associated p56lck (lck) tyrosine kinase molecules, might paradoxically interfere with CD4 signaling and so might affect TCR expression in immature CD4+CD8+ thymocytes. To do so, we utilized CD4 transgenic (CD4-Tg) mice expressing a CD4 transgene controlled by the lck proximal promoter (line 727) and that markedly overexpresses CD4 (6). Indeed, the present study reveals that the signaling competence of a surface receptor can be significantly diminished when its expression is disproportionate to that of its associated cytoplasmic signaling molecule.

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Participation of CD4 coreceptor molecules in T-cell repertoire selection

Cited by 80 publications

References 24 publications

Negative and positive selection of antigen-specific cytotoxic T lymphocytes affected by the α3 domain of MHC I molecules

Negative and positive selection of antigen-specific cytotoxic T lymphocytes affected by the α3 domain of MHC I molecules

Identification and characterization of a T-cell-specific enhancer adjacent to the murine CD4 gene.

Decreased signaling competence as a result of receptor overexpression: overexpression of CD4 reduces its ability to activate p56lck tyrosine kinase and to regulate T-cell antigen receptor expression in immature CD4+CD8+ thymocytes.

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