Over expression of Foxn1 in the bone marrow prevents age-associated perturbations in the expansion and survival of T cell progenitors (153.6)

Abstract

Abstract The thymus requires continuous seeding of progenitors from hematopoietic stem cells (HSC) in bone marrow (BM) for naïve T cell production. HSC give rise to multipotent progenitors (MPP) and their progeny common lymphoid progenitors (CLP); however, MPP are the predominant source of early T cell progenitors (ETP) in the thymus. ETP, HSC, MPP and CLP decline with age, culminating in reduced naïve T cell production. We reported that the age-associated decline in ETP is abrogated in K14-Foxn1 transgenic mice (Foxn1Tg). Here, we show that Foxn1 is expressed in BM and its expression was 98-fold higher in Foxn1Tg. Foxn1 transgene expression increased endogenous Foxn1 mRNA levels by 18- to 24-fold; Foxn1 positive cells were readily detected in the BM. We found that HSC number was 2-fold higher in young Foxn1Tg versus wild type (Wt). HSC and MPP numbers declined in aged Wt but not in Foxn1Tg. A higher percent of HSC was in S,G2/M; further, HSC and MPP in subGo from Foxn1Tg were respectively 3-fold and 4-fold reduced, suggesting inhibition of cell death. In contrast, CLP frequency was 4-fold less in young Foxn1Tg. A higher number of the committed T cell progenitors (CTP) with a 2-fold increase in S,G2/M fraction were found in young Foxn1Tg versus Wt. Our data provide evidence linking Foxn1 to the development of T cell progenitors in the BM and thymus, suggesting that increased expression could limit the decline in naïve T cell production with age.