al and Lenz et al5). Despite spectacular advances since the introduction of rituximab,
many patients with advanced disease and ahigh Follicular Lymphoma International
Prognostic Index (FLIPI) score have disease
recurrences.6 For such patients, the continued study of autologous transplantation,
possibly in combination with rituximab forin vivo purging, remains an important areaof investigation. ■REFERENCES
1. Lenz G, Dreyling M, Schiegnitz E, et al. Myeloablative
radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study
Group. Blood. 2004;104:2667-2674.
2. Deconinck E, Foussard C, Milpied N, et al. High-dosetherapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patientswith advanced follicular lymphoma: a randomized multicenter study by GOELAMS. Blood. 2005;105:3817-3823.
3. Gisselbrecht C, Lepage E, Molina T, et al. Shortened
first-line high-dose chemotherapy for patients with poorprognosis aggressive lymphoma. J Clin Oncol. 2002;20:2472-2479.
4. Schouten HC, Qian W, Kvaloy S, et al. High-dosetherapy improves progression-free survival and survival in
relapsed follicular non-Hodgkin’s lymphoma: results fromthe randomized European CUP trial. J Clin Oncol. 2003;
21:3918-3927.
5. Lenz G, Dreyling M, Unterhalt M, Hiddemann W. In
reply [letter]. J Clin Oncol. 2005;23:6264-6266.
6. Buske C, Hoster E, Dreyling M, et al. The FollicularLymphoma International Prognostic Index (FLIPI) separates high-risk from intermediate- or low-risk patients withadvanced-stage follicular lymphoma treated front-line withrituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with respect to treatment outcome. Blood. 2006;108:1504-1508.

● ● ● CHEMOKINES, CYTOKINES, AND INTERLEUKINS

Comment on Liu et al, page 2531

Thymus colonization: a shared
responsibility---------------------------------------------------------------------------------------------------------------Graham Anderson MRC CENTRE FOR IMMUNE REGULATION

Chemokine production by thymic epithelial cells has been implicated in the recruitment of T-cell progenitors to the thymus. Here, Liu and colleagues show cooperation between the thymus and the parathyroid in chemokine-mediated thymus
colonization.
supports the development of lymphoid precursors, these cells are produced in extrathymic tissues and have to undergo a migratory
journey culminating in thymus seeding. The
mechanisms regulating thymus colonization
are not clear, and it is likely that progenitors
enter the thymus indifferent ways during
development. For example, in the embryo,lymphoid precursors
can enter prior to thymus vascularization,
whereas at later stages,
cells enter the thymus
via the circulation.1,2
Liu et al analyzed
the first wave of progenitors to colonize theprevascularized thyChemokine expression and fetal thymus colonization: a role for the paramus rudiment, which
thyroid. See the complete figure in the article beginning on page 2531.
n this issue of Blood, Liu and colleagues
have analyzed the mechanisms that regulate
the recruitment of lymphoid precursors to thethymus. This a is a critical step in the production of T cells, as although the thymus provides a specialized microenvironment thatIblood 1 5 O C T O B E R 2 0 0 6 I V O L U M E 1 0 8 , N U M B E R 8

is notable in that these progenitors are able togenerate a specialized subset of epidermal ␥␦T cells that regulate immune responses in theskin.3 By carefully analyzing progenitor recruitment in embryos deficient in particularchemokine receptors, the authors show thatthe attraction of lymphoid precursors to theprevascular thymus anlagen depends upon
their expression of CCR9 and CCR7. In contrast, following thymus vascularization,
CCR7/CCR9 double-deficient precursors areable to enter the thymic microenvironment, afinding that directly demonstrates temporallyregulated mechanisms of thymus seeding.
As these findings suggested a role for theligands of these receptors, CCL25 (for CCR9)and CCL19/21 (for CCR7), in early thymus
colonization, the authors went on to analyze
chemokine expression in the early thymic anlagen. Perhaps surprisingly, immunohistochemical analysis demonstrated anatomic
compartmentalization of chemokine expression within the third pharyngeal pouch (seefigure). Thus, while CCL25 was detected at 2sites, the ventral-posterior domain that givesrise to the thymus and the dorsal-anterior domain that forms the parathyroid, CCL21 expression was detected only in the parathyroid
region (see figure). Moreover, at embryonicday 11.5, the initial attraction of lymphoidprogenitors in FoxN1-deficient nude mice,
which lack thymic production of CCL25, occurred normally. Collectively, these findings
identify CCR9 and CCR7 as key chemokine
receptors regulating recruitment of progenitors to the prevascular thymic anlagen anddemonstrate a previously unrecognized synergy between the parathyroid and the thymus inchemokine-mediated recruitment of lymphoidprogenitors. ■REFERENCES
1. Takahama T. Journey through the thymus: stromal
guides for T-cell development and selection. Nat Rev Immunol. 2006;6:127-135.
2. Petrie HT. Cell migration and the control of post-natal
T-cell lymphopoiesis in the thymus. Nat Rev Immunol.
2003;3:859-866.
3. Giradi M, Lewis J, Glusac E, et al. Resident skin-specific␥␦ T-cells provide local, nonredundant regulation of cutaneous inflammation. J Exp Med. 2002;195:855-867.

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