Multicongenic fate mapping quantification of dynamics of thymus colonization.
Postnatal T cell development depends on continuous colonization of the thymus by BM-derived T lineage progenitors. Both quantitative parameters and the mechanisms of thymus seeding remain poorly understood. Here, we determined the number of dedicated thymus-seeding progenitor niches (TSPNs) capable of supporting productive T cell development, turnover rates of niche occupancy, and feedback mechanisms. To this end, we established multicongenic fate mapping combined with mathematical modeling to quantitate individual events of thymus colonization. We applied this method to study thymus colonization in CCR7(-/-)CCR9(-/-) (DKO) mice, whose TSPNs are largely unoccupied. We showed that ∼160-200 TSPNs are present in the adult thymus and, on average, 10 of these TSPNs were open for recolonization at steady state. Preconditioning of wild-type mice revealed a similar number of TSPNs, indicating that preconditioning can generate space efficiently for transplanted T cell progenitors. To identify potential cellular feedback loops restricting thymus colonization, we performed serial transfer experiments. These experiments indicated that thymus seeding was directly restricted by the duration of niche occupancy rather than long-range effects, thus challenging current paradigms of thymus colonization.
Institute of Immunology, Hannover Medical School, D-30625 Hannover, Germany Krueger.Andreas@mh-hannover.de Natalia.Zietara@med.uni-muenchen.de.
Natalia
N
Ziętara
Institute of Immunology, Hannover Medical School, D-30625 Hannover, Germany.
Marcin
M
Łyszkiewicz
Dr. von Haunersches Kinderspital, University Children's Hospital, Ludwig Maximilian University, D-80337 Munich, Germany.
Jacek
J
Puchałka
Institute of Immunology, Hannover Medical School, D-30625 Hannover, Germany.
Katrin
K
Witzlau
Institute of Immunology, Hannover Medical School, D-30625 Hannover, Germany.
Annika
A
Reinhardt
Institute of Immunology, Hannover Medical School, D-30625 Hannover, Germany.
Reinhold
R
Förster
Institute of Immunology, Hannover Medical School, D-30625 Hannover, Germany Institute of Molecular Medicine, RWTH Aachen University, D-52074 Aachen, Germany.
Oliver
O
Pabst
Institute of Immunology, Hannover Medical School, D-30625 Hannover, Germany.
Immo
I
Prinz
Institute of Immunology, Hannover Medical School, D-30625 Hannover, Germany Krueger.Andreas@mh-hannover.de Natalia.Zietara@med.uni-muenchen.de.
Andreas
A
Krueger
D000818:Animals; D019070:Cell Lineage; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054388:Receptors, CCR / Q000235:genetics / Q000378:metabolism; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000235:genetics; D013234:Stem Cells / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology*; D060168:Thymocytes / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology* / Q000502:physiology / Q000528:radiation effects
C119309:CC chemokine receptor 9; C515371:Ccr7 protein, mouse; C491673:Il17ra protein, mouse; D054388:Receptors, CCR; D054400:Receptors, CCR7; D053722:Receptors, Interleukin-17