Mathematical modeling of oncogenesis control in mature T-cell populations
T-cell receptor (TCR) polyclonal mature T cells are surprisingly resistant to oncogenic transformation after retroviral insertion of T-cell oncogenes. In a mouse model, it has been shown that mature T-cell lymphoma / leukemia (MTCLL) is not induced upon transplantation of mature, TCR polyclonal wild...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2013-11-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fimmu.2013.00380/full |
| _version_ | 1818545404852043776 |
|---|---|
| author | Sebastian eGerdes Sebastian eNewrzela Ingmar eGlauche Dorothee evon Laer Martin-Leo eHansmann Ingo eRoeder |
| author_facet | Sebastian eGerdes Sebastian eNewrzela Ingmar eGlauche Dorothee evon Laer Martin-Leo eHansmann Ingo eRoeder |
| author_sort | Sebastian eGerdes |
| collection | DOAJ |
| description | T-cell receptor (TCR) polyclonal mature T cells are surprisingly resistant to oncogenic transformation after retroviral insertion of T-cell oncogenes. In a mouse model, it has been shown that mature T-cell lymphoma / leukemia (MTCLL) is not induced upon transplantation of mature, TCR polyclonal wild-type (WT) T cells, transduced with gammaretroviral vectors encoding potent T-cell oncogenes, into RAG1-deficient recipients. However, further studiesdemonstrated that quasi-monoclonal T cells treated with the same protocol readily induced MTCLL in the recipient mice. It has been hypothesized that in the TCR polyclonal situation, outgrowth of preleukemic cells and subsequent conversion to overt malignancy is suppressed through regulation of clonal abundances on a per-clone basis due tointeractions between TCRs and self-peptide-MHC-complexes (spMHCs), while these mechanisms fail in the quasi-monoclonal situation. To quantitatively study this hypothesis, we applied a mathematical modeling approach. In particular, we developed a novel ordinary differential equation model of T-cell homeostasis, in which T-cell fate depends on spMHC-TCR-interaction-triggered stimulatory signals from antigen-presenting cells (APCs).Based on our mathematical modeling approach, we identified parameter configurations of our model,which consistently explain the observed phenomena. Our results suggest that the preleukemic cells are less competent than healthy competitor cells in acquiring survival stimuli from APCs, but that proliferation of these preleukemic cells is less dependent on survival stimuli from APCs. These predictions now call for experimental validation. |
| first_indexed | 2024-12-12T07:39:49Z |
| format | Article |
| id | doaj.art-a2c1922bf0764604888ccf84300c75a1 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T07:39:49Z |
| publishDate | 2013-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-a2c1922bf0764604888ccf84300c75a12022-12-22T00:32:49ZengFrontiers Media S.A.Frontiers in Immunology1664-32242013-11-01410.3389/fimmu.2013.0038063887Mathematical modeling of oncogenesis control in mature T-cell populationsSebastian eGerdes0Sebastian eNewrzela1Ingmar eGlauche2Dorothee evon Laer3Martin-Leo eHansmann4Ingo eRoeder5Medical Faculty Carl Gustav Carus, TU DresdenGoethe-University Hospital FrankfurtMedical Faculty Carl Gustav Carus, TU DresdenMedical University InnsbruckGoethe-University Hospital FrankfurtMedical Faculty Carl Gustav Carus, TU DresdenT-cell receptor (TCR) polyclonal mature T cells are surprisingly resistant to oncogenic transformation after retroviral insertion of T-cell oncogenes. In a mouse model, it has been shown that mature T-cell lymphoma / leukemia (MTCLL) is not induced upon transplantation of mature, TCR polyclonal wild-type (WT) T cells, transduced with gammaretroviral vectors encoding potent T-cell oncogenes, into RAG1-deficient recipients. However, further studiesdemonstrated that quasi-monoclonal T cells treated with the same protocol readily induced MTCLL in the recipient mice. It has been hypothesized that in the TCR polyclonal situation, outgrowth of preleukemic cells and subsequent conversion to overt malignancy is suppressed through regulation of clonal abundances on a per-clone basis due tointeractions between TCRs and self-peptide-MHC-complexes (spMHCs), while these mechanisms fail in the quasi-monoclonal situation. To quantitatively study this hypothesis, we applied a mathematical modeling approach. In particular, we developed a novel ordinary differential equation model of T-cell homeostasis, in which T-cell fate depends on spMHC-TCR-interaction-triggered stimulatory signals from antigen-presenting cells (APCs).Based on our mathematical modeling approach, we identified parameter configurations of our model,which consistently explain the observed phenomena. Our results suggest that the preleukemic cells are less competent than healthy competitor cells in acquiring survival stimuli from APCs, but that proliferation of these preleukemic cells is less dependent on survival stimuli from APCs. These predictions now call for experimental validation.http://journal.frontiersin.org/Journal/10.3389/fimmu.2013.00380/fullGene TherapyT-cell homeostasisT-cell nichemature T-cell lymphomaMTCL |
| spellingShingle | Sebastian eGerdes Sebastian eNewrzela Ingmar eGlauche Dorothee evon Laer Martin-Leo eHansmann Ingo eRoeder Mathematical modeling of oncogenesis control in mature T-cell populations Frontiers in Immunology Gene Therapy T-cell homeostasis T-cell niche mature T-cell lymphoma MTCL |
| title | Mathematical modeling of oncogenesis control in mature T-cell populations |
| title_full | Mathematical modeling of oncogenesis control in mature T-cell populations |
| title_fullStr | Mathematical modeling of oncogenesis control in mature T-cell populations |
| title_full_unstemmed | Mathematical modeling of oncogenesis control in mature T-cell populations |
| title_short | Mathematical modeling of oncogenesis control in mature T-cell populations |
| title_sort | mathematical modeling of oncogenesis control in mature t cell populations |
| topic | Gene Therapy T-cell homeostasis T-cell niche mature T-cell lymphoma MTCL |
| url | http://journal.frontiersin.org/Journal/10.3389/fimmu.2013.00380/full |
| work_keys_str_mv | AT sebastianegerdes mathematicalmodelingofoncogenesiscontrolinmaturetcellpopulations AT sebastianenewrzela mathematicalmodelingofoncogenesiscontrolinmaturetcellpopulations AT ingmareglauche mathematicalmodelingofoncogenesiscontrolinmaturetcellpopulations AT dorotheeevonlaer mathematicalmodelingofoncogenesiscontrolinmaturetcellpopulations AT martinleoehansmann mathematicalmodelingofoncogenesiscontrolinmaturetcellpopulations AT ingoeroeder mathematicalmodelingofoncogenesiscontrolinmaturetcellpopulations |