Dataset Information

A GMCSF and IL7 fusion cytokine leads to functional thymic-dependent T-cell regeneration in age-associated immune deficiency.

ABSTRACT: The competence of cellular immunity depends on a diverse T-cell receptor (TCR) repertoire arising from thymic output. Normal thymopoiesis arises from marrow-derived CD3(-)CD4(-)CD8(-) triple-negative T-cell progenitors (TN), which develop into mature single-positive (SP) CD4 or CD8 T cells after expressing both CD4 and CD8 (double-positive, DP) transiently, leading to de novo T-cell production. Interleukin-7 (IL7) is a singularly important common ?-chain IL involved in normal thymic development. Our previous work has demonstrated that ?c cytokines fused with granulocyte-macrophage colony stimulating factor (GMCSF) at the N-terminus acquire unheralded biological properties. Therefore, to enhance thymopoiesis, we developed a novel biopharmaceutical based on the fusion of GMCSF and IL7, hereafter GIFT7. Systemic administration of GIFT7 leads to cortical thymic hyperplasia including the specific expansion of CD44(int)CD25(-) double-negative 1 (DN1) thymic progenitors. During murine cytomegalovirus (mCMV) infection of aged animals, GIFT7-mediated neo-thymopoiesis led to increased absolute numbers of viral-specific CD8(+) T cell. Our work demonstrated that thymic precursors can be therapeutically repopulated and its reconstitution leads to meaningful central and peripheral T-cell neogenesis, correcting immune dysfunction arising from age-associated thymic atrophy.

SUBMITTER: Hsieh J

PROVIDER: S-EPMC4478872 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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A GMCSF and IL7 fusion cytokine leads to functional thymic-dependent T-cell regeneration in age-associated immune deficiency.

Hsieh Jeremy J Ng Spencer S Bosinger Steve S Wu Jian Hui JH Tharp Gregory K GK Garcia Anapatricia A Hossain Mohammad S MS Yuan Shala S Waller Edmund K EK Galipeau Jacques J

Clinical & translational immunology 20150508 5

The competence of cellular immunity depends on a diverse T-cell receptor (TCR) repertoire arising from thymic output. Normal thymopoiesis arises from marrow-derived CD3(-)CD4(-)CD8(-) triple-negative T-cell progenitors (TN), which develop into mature single-positive (SP) CD4 or CD8 T cells after expressing both CD4 and CD8 (double-positive, DP) transiently, leading to de novo T-cell production. Interleukin-7 (IL7) is a singularly important common γ-chain IL involved in normal thymic development. ...[more]

PMID: 26131365

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Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a rare form of immune-mediated interstitial lung disease characterized by progressive pulmonary fibrosis and scarring. The pathogenesis of IPF is still unclear. Gene fusion events exist universally during transcription and show alternated patterns in a variety of lung diseases. Therefore, the comprehension of the function of gene fusion in IPF might shed light on IPF pathogenesis research and facilitate treatment development.MethodsIn this study, we included 91 transcriptome datasets from the National Center for Biotechnology Information (NCBI), including 52 IPF patients and 39 healthy controls. We detected fusion events in these datasets and probed gene fusion-associated differential gene expression and functional pathways. To obtain robust results, we corrected the batch bias across different projects.ResultsWe identified 1550 gene fusion events in all transcriptomes and studied the possible impacts of IL7 = AC083837.1 gene fusion. The two genes locate adjacently in chromosome 8 and share the same promoters. Their fusion is associated with differential expression of 282 genes enriched in six Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and 35 functional gene sets. Gene ontology (GO) enrichment analysis shows that IL7 = AC083837.1 gene fusion is associated with the enrichment of 187 gene sets. The co-expression network of interleukin-7 (IL7) indicates that decreased IL7 expression is associated with many pathways that regulate IPF progress.ConclusionBased on the results, we conclude that IL7 = AC083837.1 gene fusion might exacerbate fibrosis in IPF via enhancing activities of natural killer cell-mediated cytotoxicity, skin cell apoptosis, and vessel angiogenesis, the interaction of which contributes to the development of fibrosis and the deterioration of respiratory function of IPF patients. Our work unveils the possible roles of gene fusion in regulating IPF and demonstrates that gene fusion investigation is a valid approach in probing immunologic mechanisms and searching potential therapeutic targets for treating IPF.The reviews of this paper are available via the supplemental material section.

Project description:Thymic senescence contributes to increased incidence of infection, cancer and autoimmunity at senior ages. This process manifests as adipose involution. As with other adipose tissues, thymic adipose involution is also controlled by PPARgamma. This is supported by observations reporting that systemic PPARgamma activation accelerates thymic adipose involution. Therefore, we hypothesized that decreased PPARgamma activity could prevent thymic adipose involution, although it may trigger metabolic adverse effects. We have confirmed that both human and murine thymic sections show marked staining for PPARgamma at senior ages. We have also tested the thymic lobes of PPARgamma haplo-insufficient and null mice. Supporting our working hypothesis both adult PPARgamma haplo-insufficient and null mice show delayed thymic senescence by thymus histology, thymocyte mouse T-cell recombination excision circle qPCR and peripheral blood naive T-cell ratio by flow-cytometry. Delayed senescence showed dose-response with respect to PPARgamma deficiency. Functional immune parameters were also evaluated at senior ages in PPARgamma haplo-insufficient mice (null mice do not reach senior ages due to metabolic adverse affects). As expected, sustained and elevated T-cell production conferred oral tolerance and enhanced vaccination efficiency in senior PPARgamma haplo-insufficient, but not in senior wild-type littermates according to ELISA IgG measurements. Of note, humans also show increased oral intolerance issues and decreased protection by vaccines at senior ages. Moreover, PPARgamma haplo-insufficiency also exists in human known as a rare disease (FPLD3) causing metabolic adverse effects, similar to the mouse. When compared to age- and metabolic disorder-matched other patient samples (FPLD2 not affecting PPARgamma activity), FPLD3 patients showed increased human Trec (hTrec) values by qPCR (within healthy human range) suggesting delayed thymic senescence, in accordance with mouse results and supporting our working hypothesis. In summary, our experiments prove that systemic decrease of PPARgamma activity prevents thymic senescence, albeit with metabolic drawbacks. However, thymic tissue-specific PPARgamma antagonism would likely solve the issue.

Dataset Information

A GMCSF and IL7 fusion cytokine leads to functional thymic-dependent T-cell regeneration in age-associated immune deficiency.

Publications

A GMCSF and IL7 fusion cytokine leads to functional thymic-dependent T-cell regeneration in age-associated immune deficiency.

Similar Datasets

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