Imprinting of CCR9 on CD4 T cells requires IL-4 signaling on mesenteric lymph node dendritic cells.
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-4Ralpha(-/-) 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.
Elgueta
Raul
R
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Sepulveda
Fernando E
FE
Vilches
Felipe
F
Vargas
Leonardo
L
Mora
J Rodrigo
JR
Bono
Maria Rosa
MR
Rosemblatt
Mario
M
D000445:Aldehyde Oxidoreductases; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression; D015847:Interleukin-4 / Q000276:immunology* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008643:Mesentery / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D054388:Receptors, CCR / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
C119309:CC chemokine receptor 9; D054388:Receptors, CCR; D015847:Interleukin-4; D000445:Aldehyde Oxidoreductases; C470579:RALDH2 protein, mouse