Abstract
The thymus reaches its maximum size early in life and then begins to shrink, producing fewer T cells with increasing age. This thymic decline is thought to contribute to age-related T cell lymphopenias and hinder T cell recovery after bone marrow transplantation. Although several cellular and molecular processes have been implicated in age-related thymic involution, their relative contributions are not known. Using heterochronic parabiosis, we observe that young circulating factors are not sufficient to drive regeneration of the aged thymus. In contrast, we find that resupplying young, engraftable thymic epithelial cells (TECs) to a middle-aged or defective thymus leads to thymic growth and increased T cell production. Intrathymic transplantation and in vitro colony-forming assays reveal that the engraftment and proliferative capacities of TECs diminish early in life, whereas the receptivity of the thymus to TEC engraftment remains relatively constant with age. These results support a model in which thymic growth and subsequent involution are driven by cell-intrinsic changes in the proliferative capacity of TECs, and further show that young TECs can engraft and directly drive the growth of involuted thymuses.
Footnotes
This work was supported by a Mary K. Iacocca Foundation Research Fellowship (to M.-J.K.), a Harvard Stem Cell Institute seed grant and a Harvard Stem Cell Institute program project grant (to T.S.), The Peabody Foundation (to T.S.), the Alexander and Margaret Stewart Trust (to T.S.), The Fleischer Foundation (to T.S.), The Pittsburgh Foundation (to T.S.), the Glenn Foundation for Medical Research (to A.J.W.), the National Institutes of Health (Grants 1R01 AG033053, 1DP2 OD004345, and 5U01 HL100402 to A.J.W.), and the National Institutes of Health Diabetes Research Center (Grant P30DK036836).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- cTEC
- cortical TEC
- E
- embryonic day
- EpCAM
- epithelial cell adhesion molecule
- ETP
- early thymic progenitor
- HSC
- hematopoietic stem cell
- MHCI
- MHC class I
- MHCII
- MHC class II
- mTEC
- medullary TEC
- P
- postnatal day
- PFA
- paraformaldehyde
- RFP
- red fluorescent protein
- TEC
- thymic epithelial cell
- UEA
- Ulex europaeus agglutinin I
- WT
- wild type.
- Received December 18, 2014.
- Accepted March 9, 2015.
- Copyright © 2015 by The American Association of Immunologists, Inc.