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Three Chemokine Receptors Cooperatively Regulate Homing of Hematopoietic Progenitors to the Embryonic Mouse Thymus

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Three Chemokine Receptors Cooperatively Regulate Homing of Hematopoietic Progenitors to the Embryonic Mouse Thymus Three chemokine receptors cooperatively regulate homing of hematopoietic progenitors to the embryonic mouse thymus Lesly Calderón and Thomas Boehm1 Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, D-79108 Freiburg, Germany Edited* by Max D. Cooper, Emory University, Atlanta, GA, and approved March 25, 2011 (received for review November 2, 2010) The thymus lacks self-renewing hematopoietic cells, and thymopoi- These results were interpreted as indicating that Ccr9/Ccl25 and esis fails rapidly when the migration of progenitor cells to the Ccr7/Ccl21 are essential only for the prevascular stage of thymus thymus ceases. Hence, the process of thymus homing is an essen- colonization. Interestingly, two recent reports demonstrate that tial step for T-cell development and cellular immunity. Despite de- adult mice lacking both Ccr7 and Ccr9 display severe reductions cades of research, the molecular details of thymus homing have not in the number of early thymic progenitors and suggest that been elucidated fully. Here, we show that chemotaxis is the key compensatory expansion of intrathymic populations could ex- mechanism regulating thymus homing in the mouse embryo. We plain, at least in part, normal thymic cellularity (13, 14). Although determined the number of early thymic progenitors in the thymic these studies ascribe important roles to Ccr9 and Ccr7 in thymus rudimentsofmicedeficient for one, two, or three of the chemokine colonization, these receptors do not appear to be essential, sug- receptor genes, chemokine (C-C motif) receptor 9 (Ccr9), chemokine gesting that other molecules might be involved, for instance (C-C motif) receptor 7 (Ccr7), and chemokine (C-X-C motif) receptor 4 Cxcl12 and its receptor Cxcr4. In initial analyses of Cxcr4- and (Cxcr4). In the absence of all three chemokine receptors, thymus Cxcl12-deficient mice, no defect in T-cell development was ob- homing was reduced about 100-fold both before and after vascu- served (15–17), although it was found subsequently that thymo- larization of the thymic rudiment. In the absence of only two of cyte numbers were reduced at later stages of embryonic devel- these three chemokine receptor genes, thymus homing was much opment (18, 19), and this reduction recently was attributed to less affected (only two- to 10-fold), indicating that the chemotactic the contribution of the Cxcr4/Cxcl12 signaling pathway to effi- regulation of thymus homing is remarkably robust. Our results re- cient β selection (19, 20). In medaka (Oryzias latipes) and zebra- veal the redundant roles of Ccr9, Ccr7, and Cxcr4 for thymic homing fish (Danio rerio) embryos, simultaneous interference with ccl25a and provide a framework to examine the regulation of progenitor and cxcl12 specifically and completely blocked thymopoiesis, homing in the postnatal thymus. suggesting that cxcr4/cxcl12 and ccr9/ccl25 cooperate in guiding progenitors to settle in the thymus of fish embryos (21). -cell development occurs in the thymus. Beginning at midg- In this study, we therefore examined the relative contributions Testation (1), lymphocyte progenitors migrate to the thymus of Cxcr4, Ccr9, and Ccr7 chemokine receptors in the homing of IMMUNOLOGY anlage (2, 3), and there they develop into mature T cells that T-cell progenitors to the mouse embryonic thymic rudiment. emigrate to the periphery. The colonization of the thymic rudi- ment is the essential starting point of thymopoiesis; without this Results colonization, intrathymic T-cell development does not occur. Combined Absence of Ccr9 and Cxcr4 Chemokine Receptor Genes More than 30 y ago, chemotactic mechanisms were proposed to Does Not Abolish Thymopoiesis. In lower vertebrates, the co- underlie the thymus homing process (4, 5). However, so far, no operative activities of Ccr9/Ccl25 and Cxcr4/Cxcl12 chemokine single factor has been shown to regulate this process, leading to receptor/chemokine pairs regulate thymus homing (21). To the suggestion that the combinatorial activity of many factors is examinewhetherthesameistrueforthymushomingin required (6). The nature of these factors has not yet been defined. mammals, we generated mice deficient for both Ccr9 and Cxcr4. From the earliest stages of thymus development [embryonic Because it is not possible to perform live imaging of intact day (E) 11.5–12.5] onwards, chemokines such as chemokine (C- mouse embryos, we used the number of thymocytes in the C motif) ligand 21 (Ccl21), chemokine (C-C motif) ligand 25 thymic rudiments at E14.5 and 17.5 as a surrogate parameter of (Ccl25), and chemokine (C-X-C motif) ligand 12 (Cxcl12) are thymus homing. E17.5 was the latest time point that could be expressed in the thymic anlage (7–10). Cxcl12 also is expressed in examined reliably because of embryonic lethality of Cxcr4-de- the tissue surrounding the thymus, the perithymic mesenchyme ficient mice (16, 17, 22). Unexpectedly, thymopoiesis was not (7, 10); in addition, Ccl21 is expressed in the primordium of the completely abolished in Ccr9;Cxcr4 double-deficient embryos. parathyroid (7–10). At E12.5, the receptors for Ccl21, Ccl25, and AsshowninFig.1,Ccr9 deficiency alone led to only a slight Cxcl12 chemokines (Ccr7, Ccr9, and Cxcr4, respectively) are reduction in the number of thymocytes at E14.5 and E17.5, expressed in CD45+ cells isolated from the perithymic mesen- as described previously (8, 11); the effect of Cxcr4 deficiency chyme (10). on thymocyte numbers was more pronounced, particularly at Several studies support the notion that chemokines and their E17.5. Although thymocyte numbers were reduced more sub- receptors play a role in the thymus homing process. Ccr9-deficient stantially in Ccr9;Cxcr4 double-deficient embryos (by about embryos display a reduced thymocyte number at early, but not 3.4-fold at E14.5 and 9.3-fold at E17.5) than in embryos de- later, stages of thymus development (8, 11, 12). Paucity of lymph node T cells (plt)/plt embryos, which lack functional chemokine (C-C motif) ligand 19 (Ccl19) and Ccl21 genes, and Ccr7-deficient Author contributions: L.C. and T.B. designed research; L.C. performed research; L.C. and embryos exhibit an early impairment of thymus colonization but T.B. analyzed data; and L.C. and T.B. wrote the paper. have attained normal thymic cellularity by E14.5 (9). Compound The authors declare no conflict of interest. Ccr9 and Ccr7 deficiency leads to an even stronger defect; at *This Direct Submission article had a prearranged editor. −/− −/− E11.5, thymic primordia of Ccr9 ;Ccr7 embryos are poorly 1To whom correspondence should be addressed. E-mail: [email protected]. colonized by hematopoietic cells. Nonetheless, these effects are This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. transient, because thymocyte numbers are normal at birth (8). 1073/pnas.1016428108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1016428108 PNAS | May 3, 2011 | vol. 108 | no. 18 | 7517–7522 Downloaded by guest on October 2, 2021 Total thymocytes all thymocytes express the cell-surface marker CD45 (24, 25); 7 E14.5 thus, these cells most likely include the thymic immigrants and E17.5 ) their immediate progeny. The epithelium of organ primordia 10 6 is positive for cytokeratin 8; therefore, sagittal sections were immunostained for cytokeratin 8 and CD45 to reveal the precise positions of hematopoietic cells (Fig. 2). In control embryos 5 +/− +/− +/− (Ccr9 ;Ccr4 ;Ccr7 ), CD45+ cells were located inside and around the thymic primordium but also around the parathyroid −/− +/− 4 anlage (Fig. 2A). In Ccr9-deficient embryos (Ccr9 ;Cxcr4 ; Cell Number (log +/− Ccr7 ) reduced numbers of cells were found within the thymus 3 but not around the parathyroid (Fig. 2B); in contrast, the dis- +/− −/− n 15 9 21 11 7 2 7 9 tribution of cells in Cxcr4-deficient embryos (Ccr9 ;Cxcr4 ; +/− Ccr9 +/- -/- +/- -/- Ccr7 ) appeared similar to that in controls (Fig. 2C). This Cxcr4 +/- +/- -/- -/- distribution is in keeping with the results shown in Fig. 1 and with previous observations (18). In embryos deficient for both Ccr9 Fig. 1. Combined lack of Ccr9 and Cxcr4 chemokine receptors does not −/− −/− +/− and Cxcr4 (Ccr9 ;Cxcr4 ;Ccr7 ), CD45+ cells were found abolish intrathymic T-cell development. The number of thymocytes is shown D fi for embryos of the indicated genotypes at E14.5 and E17.5. The number of mainly around the parathyroid anlage (Fig. 2 ). These ndings analyzed embryos is indicated (n). are compatible with the notion that the high levels of Ccl21 expression in the parathyroid contribute to the attraction of progenitors to the perithymic area (7, 9). Accordingly, the +/− +/− −/− ficient for either chemokine receptor gene alone, significant distribution of CD45+ cells in Ccr9 ;Cxcr4 ;Ccr7 embryos numbers of thymocytes were still detectable at both stages ex- is characterized by the conspicuous absence of hematopoietic amined (Fig. 1). These results differ from those observed in fish cells near the parathyroid and reduced numbers within and (21) and indicate that the regulation of thymus homing in mice around the thymus (Fig. 2E), a reciprocal distribution compared −/− −/− +/− −/− is more complex than in lower vertebrates. with Ccr9 ;Cxcr4 ;Ccr7 embryos (Fig. 2D). In Ccr9 ; +/− −/− +/− −/− −/− Cxcr4 ;Ccr7 and Ccr9 ;Ccr4 ;Ccr7 embryos, the thy- Chemotaxis Regulates the Distribution of Hematopoietic Precursors mus still contained CD45+ cells, albeit in reduced numbers (Fig. in the Proximity of the Common Parathyroid/Thymus Anlage. Pre- 2 F and G), showing that Ccr9 and Cxcr4 on their own are suf- vious work in mice has suggested a role for the Ccr7 chemokine ficient to sustain the homing process. Notably, triple-deficient −/− −/− −/− receptor in thymus homing (8, 9, 13, 14). Therefore, we pro- embryos (Ccr9 ;Cxcr4 ;Ccr7 ) lacked CD45+ cells in and ceeded to examine the additional role of Ccr7 in the context of around the primordia of the thymus and the parathyroid. Col- single and combined deficiencies of Ccr9 and Cxcr4. To this end, lectively, these results suggest that chemotaxis regulates the dis- + we examined the distribution of CD45 hematopoietic cells tribution of progenitor cells in and around the thymus.
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