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Gene expression profiles of age-associated clonal expansions of CD8 memory T cells

ABSTRACT: Many aged individuals develop monoclonal expansions of CD8 T cells. These expansions are derived from a CD8 memory T cell that outcompetes neighboring CD8 T cells. The molecular alterations within clonal expansions that confer this competitive advantage relative to other CD8 T cells remains unknown. These microarray experiments were designed to identify genes differentially expressed in age-associated expansions of CD8 memory T cells relative to polyclonal CD8 memory T cells found in the same aged mice. Subsequent analysis of these data identified two major types of clonal expansions, distinguished by expression level of integrin a4 mRNA and protein. Based on this classification, Expansion_rep1 belongs to the integrin a4 high subtype of clonal expansions. In contrast, reps 2, 4, and 5 belong to the integrin a4 low subtype of clonal expansions. Given the divergent biological properties of these two subtypes of clonal expansions, we have focused genes differentially expressed between Expansion_rep 2, 4, and 5 and their paired PolyclonalAged samples. Keywords: Cell type comparison of gene expression

ORGANISM(S): Mus musculus

PROVIDER: GSE11677 | GEO | 2008/08/15

SECONDARY ACCESSION(S): PRJNA106079

REPOSITORIES: GEO

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Project description:Many aged individuals develop monoclonal expansions of CD8 T cells. These expansions are derived from a CD8 memory T cell that outcompetes neighboring CD8 T cells. The molecular alterations within clonal expansions that confer this competitive advantage relative to other CD8 T cells remains unknown. These microarray experiments were designed to identify genes differentially expressed in age-associated expansions of CD8 memory T cells relative to polyclonal CD8 memory T cells found in the same aged mice. Subsequent analysis of these data identified two major types of clonal expansions, distinguished by expression level of integrin a4 mRNA and protein. Based on this classification, Expansion_rep1 belongs to the integrin a4 high subtype of clonal expansions. In contrast, reps 2, 4, and 5 belong to the integrin a4 low subtype of clonal expansions. Given the divergent biological properties of these two subtypes of clonal expansions, we have focused genes differentially expressed between Expansion_rep 2, 4, and 5 and their paired PolyclonalAged samples. Experiment Overall Design: A total of 8 samples were analyzed for gene expression using the Affymetrix mouse genome 430 2.0 microarray platform. The experimental samples of interest were age-associated clonal expansions of CD8 memory T cells. We purified four clonal expansions from four independent, aged mice (indicated as "Expansion" rep1 2, 3, 4). For each clonal expansion of CD8 memory T cells that was purified, there was a paired control in which polyclonal CD8 memory T cells were harvested from the same aged mouse (denoted as "PolyclonalAged" rep1, 2, 3, 4). These paired samples allow one to consider gene expression changes from mice which have undergone the same age-associated changes in biology. The predominant comparison this study focused on was changes in gene expression between age-associated clonal expansions of CD8 memory T cells and their paired, polyclonal CD8 memory T cells. A total of 4 of these pairs were collected.

Project description:T cells contribute to host-tumor interactions in patients with monoclonal gammopathies. Expansions of CD8+CD57+TCRVÎ²+ restricted cytotoxic T cell (CTL) clones are found in 48% of patients with multiple myeloma and confer a favorable prognosis. We now report the presence of CTL clones with varying TCRVÎ² repertoire in 70% of patients with Waldenstromâs Macroglobulinaemia (WM) (n=20). Previous nucleoside analogue (NA) therapy, associated with an increased incidence of transformation to aggressive lymphoma, significantly influenced the presence of TCRVÎ² expansions (X2=11.6; P<0.001) as 83% of patients without (n=6) and only 7% with TCRVÎ² expansions (n=14) had received NA. Clonality of CD3+CD8+CD57+TCRVÎ²+ restricted CTLs were confirmed by TCRVÎ² CDR3 size analysis and direct sequencing. To characterize CTL clones, samples of CD3+CD8+CD57+TCRVÎ²+ cells were profiled using DNA microarrays and the results were validated on both gene and protein level. By gene set enrichment analysis, CTL clones not only expressed genes (GZMB, PRF1, FGFBP2) from cytotoxic pathways but also genes which suppress apoptosis, inhibit proliferation, arrest cell cycle G1/S transition and activate T cells (RAS, CSK and TOB pathways). Proliferation tracking confirmed their anergic state. Our studies demonstrate the incidence, NA sensitivity and anergic nature of clonal T cells in a B cell tumor. We used microarrays to detail the global programme of gene expression underlying T cell clonal expansion and identified distinct classes of up-regulated genes during this process. Experiment Overall Design: In this study we have sought T cell clones in the blood of patients with WM and related their presence with nucleoside analog therapy and transformation. We have also sorted CD3+CD4-TCRVÎ²+CD57+ from CD3+CD4-TCRVÎ²+CD57- cells and confirmed clonality by TCRVÎ² CDR3 size determination and sequencing and used carboxy-fluorescein diacetate succinmidyl ester (CFSE) tracking to monitor proliferation of CD3+CD4-TCRVÎ²+CD57+ clones. Finally we have performed microarray analysis to search for significant differentially expressed genes and pathways in the clonally expanded CD3+CD8+TCRVÎ²+CD57+ cells, focusing on cytotoxic pathways but also identifying other dysfunctional changes in these cells. Expression of a selection of the most differentially expressed genes detected by microarray was validated at both gene (qPCR) and protein level.

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Gene expression profiles of age-associated clonal expansions of CD8 memory T cells

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