Role and Species-specific Expression of Colon T Cell Homing Receptor GPR15 in Colitis

Nguyen LP, Pan J, Dinh TT, Hadeiba H, O’Hara E 3rd, Ebtikar A, Hertweck A, Gökmen MR, Lord GM, Jenner RG, Butcher EC, Habtezion A.

Nat Immunol. 2015 Feb;16(2):207-13. doi: 10.1038/ni.3079. Epub 2014 Dec 22.

Habtezion Photo

Left to Right: Junliang Pan, Ahmad Ebtikar, Theresa Dinh, Edward O’Hara, Linh Nguyen, Eugene Butcher, Aida Habtezion and Husein Hadeiba

Recruitment of lymphocytes from circulation is a tissue- and cell-specific process that is mediated in part by chemokine receptors. GPR15, an orphan GPCR and HIV co-receptor that is structurally related to known lymphocyte trafficking receptors, is a regulatory T cell (Treg) homing receptor for the large intestine in the mouse.  In the present study, we show that GPR15 also mediates CD4 effector/memory T cell localization to the colon.  Our experiments demonstrate GPR15-dependence of inflammation in the classic CD45RB T cell transfer model of colitis, a Th1/Th17-driven model in which pathology depends on effector T cell trafficking to the colon.  In addition, we report major species differences in GPR15 expression on CD4 T cells: whereas GPR15 is expressed by Tregs, Th1, and Th17 cells in mouse, in the human colon it is preferentially displayed by Th2 cells, and is absent on Tregs.  Species differences in Th2 vs. Treg expression correlate with preferential binding of Th2-associated GATA3 vs. Treg-associated Foxp3 transcription factor binding to human and mouse GPR15 enhancers, respectively.   The differences in T effector vs. Treg expression have fundamental implications for the potential targeting of GRP15 for therapeutic intervention, and may contribute to the Th2 association with ulcerative colitis in man, in contrast to the prominence of Th1/Th17 pathology in conventional T cell-dependent mouse models. PubMed: 25531831