title: An evolutionary stability perspective on oncogenesis control in mature T-cell populations.
abstract: Here we present a mathematical model for the dynamics of oncogenesis control in mature T-cell populations within the blood and lymphatic system. T-cell homeostasis is maintained by clonal competition for trophic niches (survival signals stimulated through interactions with self-antigens bound to major histocompatibility molecules), where a clone is defined as the set of T cells carrying the same antigen specific T-cell receptor (TCR). We analytically derive fitness functions of healthy and leukemic clone variants, respectively, that capture the dependency of the stability of the healthy T-cell pool against leukemic invaders on clonal diversity and kinetic parameters. Similar to the stability of ecosystems with high biodiversity, leukemic mutants are suppressed within polyclonal T-cell populations, i.e., in the presence of a huge number of different TCRs. To the contrary, for a low clonal diversity the leukemic clone variants are able to invade the healthy T-cell pool. The model, therefore, describes the experimentally observed phenomenon that preleukemic clone variants prevail in quasi-monoclonal experimental settings (in mice), whereas in polyclonal settings the healthy TCR variants are able to suppress the outgrowth of tumours. Between the two extremal situations of mono- and polyclonality there exists a range of coexistence of healthy and oncogenic clone variants with moderate fitness (stability) each. A variation of cell cycle times considerably changes the dynamics within this coexistence region. Faster proliferating variants increase their chance to dominate. Finally, a simplified niche variation scheme illustrates a possible mechanism to increase clonal T-cell diversity given a small niche diversity.
authors.affiliation: Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Institute for Medical Informatics and Biometry, Fetscherstrasse 74, D-01307 Dresden, Germany. Electronic address: hans@diebner.de.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Diebner
authors.affiliation: Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich-Straße 51-59, 63225 Langen, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Kirberg
authors.affiliation: Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Institute for Medical Informatics and Biometry, Fetscherstrasse 74, D-01307 Dresden, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Roeder
mesh_terms: D000818:Animals; D005075:Biological Evolution; D063646:Carcinogenesis; D002453:Cell Cycle; D003198:Computer Simulation; D006706:Homeostasis; D006801:Humans; D007700:Kinetics; D015458:Leukemia, T-Cell / Q000276:immunology*; D016399:Lymphoma, T-Cell / Q000276:immunology*; D051379:Mice; D015233:Models, Statistical; D008962:Models, Theoretical; D009154:Mutation; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*
chemical_list: D011948:Receptors, Antigen, T-Cell
keywords: MTCL; Mature T-cell lymphoma; Oncogenesis control; T-cell homeostasis; T-cell niche