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Upregulation of CD4 expression during MHC class II-specific positive selection is essential for error-free lineage choice.

ABSTRACT: The lineage fate of developing thymocytes is determined by the persistence or cessation of T cell receptor (TCR) signaling during positive selection, with persistent TCR signaling required for CD4 lineage choice. We show here that transcriptional upregulation of CD4 expression is essential for error-free lineage choice during major histocompatibility complex class II (MHC II)-specific positive selection and is critical for error-free lineage choice in TCR-transgenic mice whose thymocytes compete for the identical selecting ligand. CD4 upregulation occurred for endogenously encoded CD4 coreceptors, but CD4 transgenes were downregulated during positive selection, disrupting MHC II-specific TCR signaling and causing lineage errors regardless of the absolute number or signaling strength of transgenic CD4 proteins. Thus, the kinetics of CD4 coreceptor expression during MHC II-specific positive selection determines the integrity of CD4 lineage choice, revealing an elegant symmetry between coreceptor kinetics and lineage choice.

SUBMITTER: Sarafova SD

PROVIDER: S-EPMC2758695 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Upregulation of CD4 expression during MHC class II-specific positive selection is essential for error-free lineage choice.

Sarafova Sophia D SD Van Laethem Francois F Adoro Stanley S Guinter Terry T Sharrow Susan O SO Feigenbaum Lionel L Singer Alfred A

Immunity 20090910 3

The lineage fate of developing thymocytes is determined by the persistence or cessation of T cell receptor (TCR) signaling during positive selection, with persistent TCR signaling required for CD4 lineage choice. We show here that transcriptional upregulation of CD4 expression is essential for error-free lineage choice during major histocompatibility complex class II (MHC II)-specific positive selection and is critical for error-free lineage choice in TCR-transgenic mice whose thymocytes compete ...[more]

PMID: 19747858

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Project description:The vertebrate immune response is mediated through highly adaptive, quickly evolving cell surface receptors, the major histocompatibility complex (MHC). MHC molecules bind and present a diverse array of pathogenic molecules and trigger a cascade of defenses. Use of MHC variation as a marker for population health has also evolved quickly following advances in sequencing methods. We applied a combination of traditional and next generation sequencing methodology to characterize coding (peptide binding region) and regulatory (proximal promoter) sequence variation in MHC Class II DQA and DQB genes between estuarine and coastal populations of the bottlenose dolphin, Tursiops truncatus, an apex predator whose health status is indicative of anthropogenic impacts on the ecosystem. The coding regions had 10 alleles each at DQA and DQB; the promoters had 6 and 7 alleles at DQA and DQB, respectively with variation within key regulatory motifs. Positive selection was observed for the coding regions of both genes while both coding and promoter regions exhibited geographic differences in allele composition that likely indicates diversifying selection across habitats. Most notable was the discovery of a complete duplication of a 14-bp T-box motif in the DQA promoter. Four class II promoter regions (DQA, DQB, DRA, DRB) were characterized in species from four cetacean families (Delphinidae, Monodontidae, Lipotidae, and Physeteridae) and revealed substantial promoter structural diversity across this order. Peptide binding regions may not be the only source of adaptive potential within cetacean MHC for responding to pathogenic threats. These findings are the first analysis of cetacean MHC regulatory motifs, which may divulge unique immunogenetic strategies among cetaceans and reveal how MHC transcriptional control continues to evolve. The combined MHC regulatory and coding data provide new genetic context for distinct vulnerability profiles between coastal and estuarine populations, which are key concerns for health and risk management.

Dataset Information

Upregulation of CD4 expression during MHC class II-specific positive selection is essential for error-free lineage choice.

Publications

Upregulation of CD4 expression during MHC class II-specific positive selection is essential for error-free lineage choice.

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