Transforming growth factor-beta2 is involved in quantitative genetic variation in thymic involution.
The mechanisms regulating thymic involution are unclear. In inbred mouse strains the rate of thymic involution and the function of the hematopoietic stem cell (HSC) compartment are subject to quantitative genetic variation. We have shown previously that transforming growth factor-beta2 (TGF-beta2) is a genetically determined positive regulator of HSCs. Here, we demonstrate that genetic variation in the rate of thymic involution correlates with genetic variation in the responsiveness of hematopoietic stem and progenitor cells to TGF-beta2. Corroborating these correlations, thymic cellularity and peripheral naive T-cell frequency were higher in old Tgfb2+/- mice than in wild-type littermates. The frequency of early T-cell precursors was increased in Tgfb2+/- mice, suggesting that TGF-beta2 affects the earliest stages of T-cell development in old mice. Reciprocal transplantation experiments indicated that TGF-beta2 expressed both in the (micro)environment and in the hematopoietic system can accelerate thymic involution; however, the age of the stem cells appeared irrelevant. Thus, although thymic involution is largely determined by the aged environment, TGF-beta2 plays a major modulatory role that is subject to genetic variation and is possibly mediated through its regulatory effects on early hematopoiesis.
Kumar
Ritu
R
Department of Cell and Gene Medicine, Mount Sinai School of Medicine, Box 1496, Gustave L. Levy Pl, New York, NY 10029, USA.
Langer
Jessica C
JC
Snoeck
Hans-Willem
HW
D000375:Aging / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation; D014644:Genetic Variation; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053781:Transforming Growth Factor beta2
D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2