Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Examination of inflammatory transcripts during a transfer model of type I diabetes.

ABSTRACT: In an accompanying paper we found specific localization of diabetogenic T cells only to islets of Langerhans bearing the specific antigen. Instrumental in the specific localization was the presence of intra-islet dendritic cells bearing the β-cell-peptide-MHC complex. Here we report that the entry of diabetogenic CD4 T cells very rapidly triggered inflammatory gene expression changes in islets and vessels by up-regulating chemokines and adhesion molecules. VCAM-1 expression was notable in blood vessels and so was ICAM-1. ICAM-1 was also found on β-cells. These expression changes induced the entry of non-specific T cells that otherwise did not localize to the islets. In contrast to the entry of diabetogenic CD4 T cells, the entrance of non-specific T cells required a chemokine response and VCAM-1 expression by the islets. Interferon-gamma was important for the early gene expression changes in the islets. By microarray analysis we detected up-regulation of a group of interferon-inducible genes as early as 8 hours post T cell transfer. These studies provide a baseline to examine the development of therapeutics that can modulate islet localization of diabetogenic T cells to control this autoimmune disease. 20 total samples

ORGANISM(S): Mus musculus

SUBMITTER: Emil Unanue

PROVIDER: E-GEOD-26147 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Entry of diabetogenic T cells into islets induces changes that lead to amplification of the cellular response.

Calderon Boris B Carrero Javier A JA Miller Mark J MJ Unanue Emil R ER

Proceedings of the National Academy of Sciences of the United States of America 20110110 4

In an accompanying paper, we find specific localization of diabetogenic T cells only to islets of Langerhans bearing the specific antigen. Instrumental in the specific localization was the presence of intraislet dendritic cells bearing the β-cell-peptide-MHC complex. Here, we report that the entry of diabetogenic CD4 T cells very rapidly triggered inflammatory gene expression changes in islets and vessels by up-regulating chemokines and adhesion molecules. Vascular cell adhesion molecule-1 (VCAM ...[more]

PMID: 21220309

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Project description:Melanoma recurrence frequently occurs after a latency period of several years. In vivo studies demonstrated that tumor cells overcoming latency show a T cell-edited phenotype, suggesting a relevant role for CD8+ T cells in maintaining metastatic latency. Here, in a patient model of multiple recurrent lesions, we illustrate the genetic evolution of poorly immunogenic melanoma phenotypes, evolving in the presence of autologous tumor antigen-specific CD8+ T cells. Melanoma cells from two of three late recurrent metastases, developing within a 6-year latency period, lacked HLA class I expression. HLA class I-negative tumor cells became clinically apparent 1.5 and 6 years into stage IV disease. Genome profiling by SNP arrays revealed total T-cell resistance in both metastases originating from a shared chromosome 15q alteration and independently acquired focal B2M gene deletions. A third HLA class I-positive lesion developed in year 3 of stage IV disease. By HLA haplotype loss lesion-derived melanoma cells acquired resistance towards dominant T-cell clonotypes targeting early stage III tumor cells. Early disease melanoma cells showed a dedifferentiated MITFnegative phenotype, recently described to be associated with immunosuppression, in contrast to the MITFhigh phenotype of T cell-edited tumor cells from late metastases. In summary, our study demonstrates that tumor recurrences after long-term latency develop towards T-cell resistance by independent genetic events, suggesting a mechanism of T cell-driven genetic evolution of melanoma as a means to evade immune recognition and tumor immunotherapy. Genetic alterations lead to loss of tumor antigen presentation. Cell lines were generated from tumor material, differences in T cell recognition were observed and Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from the cell lines. SNP analysis of different melanoma cell lines obtained from one melanoma patient (4 cell lines from different metastasis of one patient with matching germline DNA).

Dataset Information

Examination of inflammatory transcripts during a transfer model of type I diabetes.

Publications

Entry of diabetogenic T cells into islets induces changes that lead to amplification of the cellular response.

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