The central hypothesis of this application is that thymic involution results from age-related changes in bone marrow T cell precursors, intrathymic progenitors, and thymic stromal cells.
One aim i s to define and characterize effects intrinsic to each of these populations. A second goal is to determine how concomitant declines in the production of Growth Hormone (GH) and Insulin-Like Growth Factor-I (IGF-I), which are thymopoietic, and increases in production of sex steroids, which potentiate thymocyte death, at puberty impact on cells in the bone marrow and thymus. Studies in Aim 1 will investigate why pluripotent hematopoietic stem cells (PHSC) from old mice do not efficiently generate T cells by testing the hypothesis that their differentiation into common lymphoid progenitors (CLP) and/or more committed T cell progenitors is compromised by aging. In addition, whether or not age-related changes in the production of GH, IGF-I or sex steroids affect the size of the PHSC and CLP compartments will be determined.
Aim 2 will investigate how aging affects the pool of intrathymic progenitors. The most immature CD44+CD25- precursors in the thymus are present at a normal frequency but their maturation is blocked. Studies will determine whether this is due to intrinsic changes that accumulate in this population and/or to alterations in the balance of microenvironmental and endocrine signals that affect their growth and survival. Finally, Aim 3 will assess if and how aging affects thymic stromal cells using a newly developed, adult thymus reaggregate culture system. In addition, fetal thymic organ cultures will be used to model how age-related changes in hormone production noted above impact on the ability of thymic stromal cells to support T cell development. Taken together, the information obtained from these studies will define the basis for thymic involution and be of value in the formulation of strategies to boost cell-mediated immunity and rejuvenate the thymus in immunocompromised individuals.
| Sham, Caroline W; Chan, Ann M; Kwong, Jacky M K et al. (2012) Neuronal programmed cell death-1 ligand expression regulates retinal ganglion cell number in neonatal and adult mice. J Neuroophthalmol 32:227-37 |
| Signer, Robert A J; Montecino-Rodriguez, Encarnacion; Witte, Owen N et al. (2010) Immature B-cell progenitors survive oncogenic stress and efficiently initiate Ph+ B-acute lymphoblastic leukemia. Blood 116:2522-30 |
| Dorshkind, Kenneth; Swain, Susan (2009) Age-associated declines in immune system development and function: causes, consequences, and reversal. Curr Opin Immunol 21:404-7 |
| Signer, Robert A J; Montecino-Rodriguez, Encarnacion; Witte, Owen N et al. (2008) Aging and cancer resistance in lymphoid progenitors are linked processes conferred by p16Ink4a and Arf. Genes Dev 22:3115-20 |
| Signer, Robert A J; Montecino-Rodriguez, Encarnacion; Dorshkind, Kenneth (2007) Aging, B lymphopoiesis, and patterns of leukemogenesis. Exp Gerontol 42:391-5 |
| Min, Hyeyoung; Montecino-Rodriguez, Encarnacion; Dorshkind, Kenneth (2006) Reassessing the role of growth hormone and sex steroids in thymic involution. Clin Immunol 118:117-23 |
| Min, Hyeyoung; Montecino-Rodriguez, Encarnacion; Dorshkind, Kenneth (2006) Effects of aging on the common lymphoid progenitor to pro-B cell transition. J Immunol 176:1007-12 |
| Montecino-Rodriquez, Encarnacion; Min, Hyeyoung; Dorshkind, Kenneth (2005) Reevaluating current models of thymic involution. Semin Immunol 17:356-61 |
| Min, Hyeyoung; Montecino-Rodriguez, Encarnacion; Dorshkind, Kenneth (2005) Effects of aging on early B- and T-cell development. Immunol Rev 205:7-17 |
| Linton, Phyllis Jean; Dorshkind, Kenneth (2004) Age-related changes in lymphocyte development and function. Nat Immunol 5:133-9 |
