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Keratinocyte Growth Factor Induces Expansion of Murine Peripheral CD4⁺Foxp3⁺ Regulatory T Cells and Increases Their Thymic Output¹

Marieke Bruinsma^*, Peter L. van Soest^*, Pieter J. M. Leenen, Bart N. Lambrecht, Tom Cupedo^*, Bob Löwenberg^*, Jan J. Cornelissen^* and Eric Braakman^2,*

^* Department of Hematology, Department of Immunology, and Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

Keratinocyte growth factor (KGF) has been shown to reduce the incidence and severity of graft-versus-host disease by prevention of epithelial damage and by modulating alloreactivity. Since regulatory T cells (Treg) play a crucial role in immune modulation, we evaluated the effects of exogenous KGF on peripheral CD4⁺Foxp3⁺ Treg and the generation of Treg in the thymus of normal mice. A 3-day course of KGF induced a rapid selective increase in the number of highly suppressive CD4⁺Foxp3⁺ Treg. Blood Treg numbers remained elevated for >2 mo, but the frequency normalized after 2 wk due to a concomitant increase in CD4⁺Foxp3^– T cells. Analysis of single joint TCR excision circles frequency and Ki-67 expression in peripheral blood Treg showed that the early selective increase of Treg was predominantly accounted for by peripheral expansion. Thymectomy before KGF administration did not affect the early selective increase of Treg but abrogated the late increase in CD4⁺ T cell numbers, thereby showing its dependence on thymic output. Collectively, these results show that KGF induces an increase in blood CD4⁺Foxp3⁺ Treg numbers via two independent mechanisms. First by selective peripheral expansion of Treg and thereafter by enhanced thymic output of newly developed Treg.

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 in part supported by the Landsteiner Foundation for Blood Transfusion Research (Grant 0221).

² Address correspondence and reprint requests to Dr. Eric Braakman, Department of Hematology, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail address: e.braakman{at}erasmusmc.nl

³ Abbreviations used in this paper: KGF, keratinocyte growth factor; BMT, bone marrow transplantation; GVHD, graft-versus-host disease; RTE, recent thymic emigrant; TEC, thymic epithelial cell; sjTREC, single-joint T cell receptor excision circle; Treg, regulatory T cell; TSLP, thymic stromal lymphopoietin; DC, dendritic cell; SP, single positive.

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