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* Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile;
Millennium Institute for Fundamental and Applied Biology, Santiago, Chile;
Fundacion Ciencia para la Vida, Santiago, Chile;
Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; and
¶ Universidad Andres Bello, Santiago, Chile
It has recently been shown that IL-4 can educate dendritic cells (DC) to differentially affect T cell effector activity. In this study, we show that IL-4 can also act upon DC to instruct naive T cells to express the gut-associated homing receptor CCR9. Thus, effector T cells generated after coculture with mesenteric lymph node (MLN)-DC show a higher expression of CCR9 when activated in the presence of IL-4. In contrast, IL-4 had no effect on CCR9 expression when naive T cells were polyclonally activated in the absence of MLN-DC, suggesting that the effect of IL-4 on CCR9 expression passed through DC. Indeed, T cells activated by MLN-DC from IL-4R
–/– mice showed a much lower CCR9 expression and a greatly reduced migration to the small intestine than T cells activated by wild-type MLN-DC even in the presence of IL-4. Consistent with the finding that the vitamin A metabolite retinoic acid (RA) induces gut-homing molecules on T cells, we further demonstrate that IL-4 up-regulated retinaldehyde dehydrogenase 2 mRNA on MLN-DC, a critical enzyme involved in the synthesis of RA. Moreover, LE135, a RA receptor antagonist, blocked the increased expression of CCR9 driven by IL-4-treated MLN-DC. Thus, besides the direct effect of RA on T cell gut tropism, our results show that the induction of a gut-homing phenotype on CD4+ T cells is also influenced by the effect of IL-4 on gut-associated DC.
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 grants from Fondo Nacional de Investigación Científica y Tecnológica 1060834 and DI 03-02 from Universidad Andrés Bello (to M.R.) and Fondo Nacional de Investigación Científica y Tecnológica 1060253 (to M.R.B.). R.E. was supported by doctoral fellowships from Programa de Mejoramiento de la Calidad y Equidad en la Educacion Superior and Consejo Nacional de Ciencia y Tecnologia and a grant from the Departmento de Postgrado and Postitulo from Universidad de Chile. J.R.M. was supported in part by a Pew Fellowship and a Career Development Award from The Crohn’s & Colitis Foundation of America.
2 R.E. and F.E.S. contributed equally to this study.
3 Address correspondence and reprint requests to Dr. Mario Rosemblatt, Fundación Ciencia para la Vida, Avenida Zanartu 1482, Santiago, Chile. E-mail address: mrosembl{at}bionova.cl
4 Abbreviations used in this paper: SLO, secondary lymphoid organ; DC, dendritic cell; HI, homing index; KO, knockout; LP, lamina propria; MFI, mean fluorescence intensity; MLN, mesenteric lymph node; PLN, peripheral lymph node; PP, Peyer’s patches; RA, retinoic acid; RALDH, retinaldehyde dehydrogenase; TRITC, tetramethylrhodamine isothiocyanate.
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