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

J Immunol. 2013 Dec 1;191(11):5583-93. doi: 10.4049/jimmunol.1202278. Epub 2013 Nov 1.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Antigens, CD
  • Forkhead Transcription Factors
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Whn protein
  • delta protein