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Peripheral self-reactivity regulates antigen-specific CD8 T cell responses and cell division under physiological conditions

ABSTRACT: It is unknown how naïve CD8 T cells that harbour different and distinct T cell receptors to the same MHC-epitope combination differ in terms of their transcriptional expression profile.

ORGANISM(S): Mus musculus

PROVIDER: GSE88996 | GEO | 2017/02/09

SECONDARY ACCESSION(S): PRJNA349472

REPOSITORIES: GEO

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TCR-MHC Interaction Strength Defines Trafficking and Resident Memory Status of CD8 T cells in the Brain.

Project description:It is unknown how peptide-activated CD8 T cells that harbour different and distinct T cell receptors to the same MHC-epitope combination differ in terms of their transcriptional expression profile.

2018-06-21 | GSE113827 | GEO

Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions.

Project description:T-cell identity is established by the expression of a clonotypic T-cell receptor (TCR), generated by somatic rearrangement of TCR? and ? genes. The properties of the TCR determine both the degree of self-reactivity and the repertoire of antigens that can be recognized. For CD8 T cells, the relationship between TCR identity-hence reactivity to self-and effector function(s) remains to be fully understood and has rarely been explored outside of the H-2b haplotype. We measured the affinity of three structurally distinct CD8 T-cell-derived TCRs that recognize the identical H-2 Ld-restricted epitope, derived from the Rop7 protein of Toxoplasma gondii We used CD8 T cells obtained from mice generated by somatic cell nuclear transfer as the closest approximation of primary T cells with physiological TCR rearrangements and TCR expression levels. First, we demonstrate the common occurrence of secondary rearrangements in endogenously rearranged loci. Furthermore, we characterized and compared the response of Rop7-specific CD8 T-cell clones upon Toxoplasma gondii infection as well as effector function and TCR signalling upon antigenic stimulation in vitro Antigen-independent TCR cross-linking in vitro uncovered profound intrinsic differences in the effector functions between T-cell clones. Finally, by assessing the degree of self-reactivity and comparing the transcriptomes of naive Rop7 CD8 T cells, we show that lower self-reactivity correlates with lower effector capacity, whereas higher self-reactivity is associated with enhanced effector function as well as cell cycle entry under physiological conditions. Altogether, our data show that potential effector functions and basal proliferation of CD8 T cells are set by self-reactivity thresholds.

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Autoimmune peptide antigen reactivity in BXD2 mice with spontaneous systemic autoimmune disease

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Autoimmune peptide antigen reactivity in BXD2 mice with spontaneous systemic autoimmune disease

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Antigen presentation by B cells enables epitope spreading across an MHC barrier

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Molecular crowding favors reactivity of a human ribozyme under physiological ionic conditions.

Project description:In an effort to relate RNA folding to function under cellular-like conditions, we monitored the self-cleavage reaction of the human hepatitis delta virus-like CPEB3 ribozyme in the background of physiological ionic concentrations and various crowding and cosolute agents. We found that at physiological free Mg(2+) concentrations (?0.1-0.5 mM), both crowders and cosolutes stimulate the rate of self-cleavage, up to ?6-fold, but that in 10 mM Mg(2+) (conditions widely used for in vitro ribozyme studies) these same additives have virtually no effect on the self-cleavage rate. We further observe a dependence of the self-cleavage rate on crowder size, wherein the level of rate stimulation is diminished for crowders larger than the size of the unfolded RNA. Monitoring effects of crowding and cosolute agents on rates in biological amounts of urea revealed additive-promoted increases at both low and high Mg(2+) concentrations, with a maximal stimulation of more than 10-fold and a rescue of the rate to its urea-free values. Small-angle X-ray scattering experiments reveal a structural basis for this stimulation in that higher-molecular weight crowding agents favor a more compact form of the ribozyme in 0.5 mM Mg(2+) that is essentially equivalent to the form under standard ribozyme conditions of 10 mM Mg(2+) without a crowder. This finding suggests that at least a portion of the rate enhancement arises from favoring the native RNA tertiary structure. We conclude that cellular-like crowding supports ribozyme reactivity by favoring a compact form of the ribozyme, but only under physiological ionic and cosolute conditions.

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