Thymic Selection of Cytotoxic T Cells Independent of CD8 α-Lck Association

Chan, Iris T.; Limmer, Andreas; Louie, Marjorie C.; Bullock, E D; Fung-Leung, Wai-Ping; Mak, Tak W.; Loh, Dennis Y.

doi:10.1126/science.8372352

Cited by 58 publications

(22 citation statements)

References 33 publications

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“…Therefore, the primary function of CD8 might be to stabilize binding of the TCR with MHC class I without overt or prolonged involvement of Ick, although we cannot exclude the involvement of other signaling molecules with CD8. The observations that transgeneencoded CD8a polypeptides with mutated lck binding motifs efficiently restore selection of CD8 SP cells in CD8a knockout mice support this view [55]. More difficult to reconcile are experiments which show that CD8 SP cell differentiation can be restored in fi2m-/-mice by constitutive expression of a CD4 transgene [9, 561.…”

Section: Discussionmentioning

confidence: 85%

Signals through CD8 or CD4 can induce commitment to the CD4 lineage in the thymus

et al. 1997

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Differentiation of thymocytes into mature single-positive T cells is an ordered process involving sequential interactions between T cell receptor (TCR), co-receptors (CD4 or CD8) and their appropriate major histocompatibility complex-encoded ligands. Precisely how these receptor/co-receptor engagements determine lineage commitment is still controversial, but recently it has been suggested that quantitative differences in the signal transmitted by co-ligation of CD4 versus CD8 with TCR might provide the discriminating signal. We examine this hypothesis, using bispecific F(ab')2 antibodies to mimic TCR/ co-receptor engagement during thymocyte differentiation. These bispecific antibodies lack Fc and can engage surface molecules without extensive cross-linking or targeting to Fc receptor-bearing cells. We show that TCR/CD3 co-ligation with CD4 induces efficient differentiation of mature CD4 lineage cells, irrespective of their TCR specificity. Interestingly, TCR/CD3 co-ligation with CD8 also induces maturation of CD4 T cells, although less efficiently, but not of CD8 T cells. Thus, although the signals delivered by co-ligation of TCR and CD8 appear weaker than from co-ligation of TCR and CD4, the outcome from either engagement is the same. These data suggest that differences in signal intensity alone do not determine lineage commitment in the thymus, but that distinct signals are required for CD4 and CD8 single-positive cell differentiation.

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Section: Discussionmentioning

confidence: 85%

Signals through CD8 or CD4 can induce commitment to the CD4 lineage in the thymus

et al. 1997

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“…Transgenic mice expressing a tailless form of CD8␣ (CD8 Ϫ / Ϫ background) have a more severe phenotype than do mice carrying a transgene in which the CXCP motif was altered by mutagenesis. Overall, CD8␣ tailless mice have three to four times fewer CD8 ϩ peripheral T cells, and their ability to mount an efficient antiviral CTL-mediated response is reduced in comparison to the CXCP mutated mice, suggesting that other factors with signaling capabilities might associate with the cytoplasmic domain (4,39,40). Recently, Trede and Zon (41) described in situ staining patterns within the zebra fish thymus using an lck probe, thus an lck homologue is present in teleost fish.…”

Section: Discussionmentioning

confidence: 99%

Description of an Ectothermic TCR Coreceptor, CD8α, in Rainbow Trout

Hansen¹,

Strassburger²

2000

The Journal of Immunology

121

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We have cloned the first CD8α gene from an ectothermic source using a degenerate primer for Ig superfamily V domains. Similar to homologues in higher vertebrates, the rainbow trout CD8α gene encodes a 204-aa mature protein composed of two extracellular domains including an Ig superfamily V domain and hinge region. Differing from mammalian CD8α V domains, lower vertebrate (trout and chicken) sequences do not contain the extra cysteine residue (C strand) involved in the abnormal intrachain disulfide bridging within the CD8α V domain of mice and rats. The trout membrane proximal hinge region contains the two essential cysteine residues involved in CD8 dimerization (αα or αβ) and threonine, serine, and proline residues which may be involved in multiple O-linked glycosylation events. Although the transmembrane region is well conserved in all CD8α sequences analyzed to date, the putative trout cytoplasmic region differs and, in fact, lacks the consensus p56lck motif common to other CD8α sequences. We then determined that the trout CD8α genomic structure is similar to that of humans (six exons) but differs from that of mice (five exons). Additionally, Northern blotting and RT-PCR demonstrate that trout CD8α is expressed at high levels within the thymus and at weaker levels in the spleen, kidney, intestine, and peripheral blood leukocytes. Finally, we show that trout CD8α can be expressed on the surface of cells via transfection. Together, our results demonstrate that the basic structure and expression of CD8α has been maintained for more than 400 million years of evolution.

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“…Ϫ or CD8-deficient mice (20,21). However, it should be noted that both of these reports relied on overexpression of coreceptor transgenes to restore development of the appropriate lineage.…”

Section: Discussionmentioning

confidence: 99%

“…Mutated forms of the CD4 or CD8 coreceptors that are unable to bind to Lck can nonetheless promote development of both helper and cytotoxic T cells, suggesting that the Lck-coreceptor interaction may not be critical for coreceptor function at the DP to SP transition (20,21). However, it should be noted that these experiments relied on dramatic overexpression of the mutant coreceptors to restore development of the lineage under investigation.…”

Section: /Cd4mentioning

confidence: 97%

Positive and Negative Selection of Thymocytes Depends on Lck Interaction with the CD4 and CD8 Coreceptors

Trobridge

Forbush

Levin

2001

The Journal of Immunology

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Considerable evidence supports a role for the Src family protein tyrosine kinase Lck in regulating multiple aspects of thymocyte development. In this report, we establish that early events in T lymphopoiesis are restored to Lck-deficient mice by provision of a transgene encoding a version of Lck that cannot interact with the coreceptors CD4 and CD8. In addition, we demonstrate that later events in thymocyte development, specifically, the processes of positive and negative selection, are compromised in mice where the only Lck available cannot associate with either CD4 or CD8. We conclude that not only is Lck activity required for positive and negative selection, but that that activity must be coupled to the CD4 and CD8 coreceptors.

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Thymic Selection of Cytotoxic T Cells Independent of CD8 α-Lck Association

Cited by 58 publications

References 33 publications

Signals through CD8 or CD4 can induce commitment to the CD4 lineage in the thymus

Signals through CD8 or CD4 can induce commitment to the CD4 lineage in the thymus

Description of an Ectothermic TCR Coreceptor, CD8α, in Rainbow Trout

Positive and Negative Selection of Thymocytes Depends on Lck Interaction with the CD4 and CD8 Coreceptors

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