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Flt3 Ligand Expands Lymphoid Progenitors Prior to Recovery of Thymopoiesis and Accelerates T Cell Reconstitution after Bone Marrow Transplantation¹

Evert-Jan Wils^*, Eric Braakman^*, Georges M. G. M. Verjans, Elwin J. C. Rombouts^*, Annoek E. C. Broers^*, Hubert G. M. Niesters, Gerard Wagemaker^*, Frank J. T. Staal, Bob Löwenberg^*, Hergen Spits and Jan J. Cornelissen^2,*

Departments of ^* Hematology, Virology, and Immunology, Erasmus Medical Center, Rotterdam, The Netherlands; and Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, The Netherlands

Deficient thymopoiesis and retarded recovery of newly developed CD4⁺ T cells is one of the most important determinants of impaired immunocompetence after hemopoietic stem cell transplantation. Here we evaluated whether Fms-like tyrosine kinase 3 (Flt3) ligand (FL) alone or combined with IL-7 affects T cell recovery, thymopoiesis, and lymphoid progenitor expansion following bone marrow transplantation in immunodeficient mice. FL strongly accelerated and enhanced the recovery of peripheral T cells after transplantation of a low number of bone marrow cells. An additive effect on T cell recovery was not observed after coadministration of IL-7. Lineage^–sca-1⁺c-kit⁺flt3⁺ lymphoid progenitor cell numbers were significantly increased in bone marrow of FL-treated mice before recovery of thymopoiesis. Thymocyte differentiation was advanced to more mature stages after FL treatment. Improved T cell recovery resulted in better immunocompetence against a post-bone marrow transplantation murine CMV infection. Collectively, our data suggest that FL promotes T cell recovery by enhanced thymopoiesis and by expansion of lymphoid progenitors.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant EMCR 2002-2694 from the Dutch Cancer Society.

² Address correspondence and reprints requests to Dr. Jan J. Cornelissen, Department of Hematology, Erasmus Medical Center/Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands. E-mail address: j.cornelissen{at}erasmusmc.nl

³ Abbreviations used in this paper: HSCT, hemopoietic stem cell transplantation; BMC, bone marrow cells; BMT, bone marrow transplantation; CLP, common lymphoid progenitor; DN, double negative; SP, single-positive; DC, dendritic cell; ETP, early T lineage progenitors; FL, Fms-like tyrosine kinase 3 ligand; HPE, homeostatic peripheral expansion; LSK cells, Lineage (Lin)^–Sca-1⁺c-Kit⁺ cells; mCMV, murine CMV; RQ-PCR, real time quantitative PCR; sjTREC, signal joint TCR excision circle; TCD, T cell depleted.

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