title: Clonally diverse T cell homeostasis is maintained by a common program of cell-cycle control.
abstract: Lymphopenia induces T cells to undergo cell divisions as part of a homeostatic response mechanism. The clonal response to lymphopenia is extremely diverse, and it is unknown whether this heterogeneity represents distinct mechanisms of cell-cycle control or whether a common mechanism can account for the diversity. We addressed this question by combining in vivo and mathematical modeling of lymphopenia-induced proliferation (LIP) of two distinct T cell clonotypes. OT-I T cells undergo rapid LIP accompanied by differentiation that superficially resembles Ag-induced proliferation, whereas F5 T cells divide slowly and remain naive. Both F5 and OT-I LIP responses were most accurately described by a single stochastic division model where the rate of cell division was exponentially decreased with increasing cell numbers. The model successfully identified key biological parameters of the response and accurately predicted the homeostatic set point of each clone. Significantly, the model was successful in predicting interclonal competition between OT-I and F5 T cells, consistent with competition for the same resource(s) required for homeostatic proliferation. Our results show that diverse and heterogeneous clonal T cell responses can be accounted for by a single common model of homeostasis.
authors.affiliation: Institute of Child Health, University College London, London, WC1N 1EH, United Kingdom.
authors.forename: Thea
authors.initials: T
authors.lastname: Hogan
authors.forename: Andrey
authors.initials: A
authors.lastname: Shuvaev
authors.forename: Daniel
authors.initials: D
authors.lastname: Commenges
authors.forename: Andrew
authors.initials: A
authors.lastname: Yates
authors.forename: Robin
authors.initials: R
authors.lastname: Callard
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Thiebaut
authors.forename: Benedict
authors.initials: B
authors.lastname: Seddon
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002999:Clone Cells; D006706:Homeostasis / Q000276:immunology*; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018448:Models, Immunological; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000637:transplantation*
chemical_list: D011948:Receptors, Antigen, T-Cell