Enhancing T lineage production in aged mice: a novel function of Foxn1 in the bone marrow niche

• Published in: The Journal of immunology (1950) Vol. 191; no. 11; pp. 5583 - 5593
• Main Authors: Zook, Erin C, Zhang, Shubin, Gerstein, Rachel M, Witte, Pamela L, Le, Phong T
• Format: Journal Article
• Language: English
• Published: United States 01.12.2013
• Subjects: Aging - immunology; Animals; Antigens, CD - metabolism; B-Lymphocytes - immunology; Bone Marrow - immunology; Cell Differentiation - genetics; Cell Differentiation - physiology; Cell Lineage - genetics; Cell Lineage - physiology; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - immunology; Forkhead Transcription Factors - metabolism; Immunophenotyping; Intracellular Signaling Peptides and Proteins - metabolism; Lymphocyte Count; Lymphoid Progenitor Cells - immunology; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Stem Cell Niche - immunology; T-Lymphocytes - immunology; Transgenes - genetics
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1202278

Foxn1 is essential for thymic organogenesis and T lymphopoiesis. Whereas reduced Foxn1 expression results in a decline in T lymphopoiesis, overexpression of Foxn1 in the thymus of a transgenic mouse model (Foxn1Tg) attenuates the age-associated decline in T lymphopoiesis. T lymphopoiesis begins with early T cell progenitors (ETP), derived from multipotent progenitors (MPP) in the bone marrow (BM). A decline in MPP and ETP numbers with age is thought to contribute to reduced T lymphopoiesis. Previously, we showed that reduced ETP number with age is attenuated in Foxn1 transgenic (Tg); whether the effect is initiated in the BM with MPP is not known. In this study, we report that Foxn1 is expressed in wild-type BM and overexpressed in Foxn1Tg. With age, the number of MPP in Foxn1Tg was not reduced, and Foxn1Tg also have a larger pool of hematopoietic stem cells. Furthermore, the Foxn1Tg BM is more efficient in generating MPP. In contrast to MPP, common lymphoid progenitors and B lineage cell numbers were significantly lower in both young and aged Foxn1Tg compared with wild type. We identified a novel population of lineage(neg/low), CD45(pos) EpCAM(pos), SCA1(pos), CD117(neg), CD138(neg), MHCII(neg) cells as Foxn1-expressing BM cells that also express Delta-like 4. Thus, Foxn1 affects both T lymphopoiesis and hematopoiesis, and the Foxn1 BM niche may function in skewing MPP development toward T lineage progenitors.