Identification of a bone marrow precursor of the earliest thymocytes in adult mouse

Anne Y. Lai and
Motonari Kondo*

Department of Immunology, Duke University Medical Center, 101 Jones Building, DUMC Box 3010, Research Drive, Durham, NC 27710

Edited by Dan R. Littman, New York University Medical Center, New York, NY, and approved February 27, 2007 (received for review October 30, 2006)

Abstract

The thymus requires continuous replenishment of progenitors from the bone marrow (BM) to sustain T cell development. However, it remains unclear which hematopoietic progenitors downstream from hematopoietic stem cells in the BM home to the thymus in adult mice. In this work, we demonstrate that although multiple BM populations have intrinsic T lineage differentiation potential, a small subset of multipotent progenitors (MPPs) expressing CCR9 preferentially homes to the thymus. These CCR9⁺ MPPs are phenotypically similar to the most immature early T lineage progenitors (ETPs) in the thymus and are present in the peripheral blood. Similar to ETPs, CCR9⁺ MPPs undergo Notch signaling, as indicated by higher expression of Notch1 and downstream target Hes1 genes compared with other MPP subsets. Furthermore, CCR9⁺ MPPs possess differentiation potential similar to that of ETPs, with very limited granulocyte/macrophage differentiation potential, but they can differentiate into T, B, and dendritic cells. These characteristics implicate CCR9⁺ MPPs as the BM precursors of the earliest thymic progenitors. In addition, our data suggest that before transition from BM to thymus, MPPs are lymphoid-specified and primed for T lineage differentiation.

Footnotes

*To whom correspondence should be addressed. E-mail: motonari.kondo{at}duke.edu
Author contributions: A.Y.L. and M.K. designed research; A.Y.L. performed research; A.Y.L. and M.K. analyzed data; and A.Y.L. and M.K. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0609608104/DC1.
Abbreviations:

BM,

bone marrow;

CLP,

common lymphoid progenitor;

DC,

dendritic cell;

DN,

double negative;

ELP,

early lymphoid progenitor;

ETP,

early T lineage progenitor;

GM,

granulocyte/macrophage;

GMP,

granulocyte/macrophage progenitor;

HSC,

hematopoietic stem cell;

KI,

knockin;

KO,

knockout;

MPP,

multipotent progenitor;

PB,

peripheral blood;

PSGL-1,

P-selectin glycoprotein ligand 1;

VCAM-1,

vascular cell adhesion molecule 1.