4th Annual BMRP Investigator Meeting - Abstract

Phenotypic and Functional Characterization of CCR9+ T Lymphocytes in Small Intestinal Crohn’s Disease

Qi T. Yu, Masayuki Saruta and Konstantinos A. Papadakisa

Department of Medicine, Inflammatory Bowel Disease Center, Burns and Allen Research Institute, Cedars-Sinai Medical Center (Los Angeles, California, U.S.A.)

The chemokine receptor CCR9 and its ligand thymus-expressed chemokine (TECK/CCL25) play a critical role for the selective homing of T lymphocytes to the small bowel (SB).  In this report, we have characterized the phenotype and cytokine profile of CCR9+ T lymphocytes in SB Crohn’s disease (CD).  Compared to normal donors, patients with SB CD show an increased percentage of CCR9+ T cells in the circulation and draining mesenteric lymph nodes (MLN) with an activated phenotype.  Analysis of cytokine production in both LPL and MLN showed a predominant Th1 cytokine profile among CCR9+ T cells in both CD and normal donors when analyzed by intracellular cytokine staining and global T cell activation with PMA plus ionomycin.  However, SB CCR9+ T cells from CD mucosa showed an enhanced production of IFN-γ as assessed by ELISA in response to TCR, CD2 or cytokine stimulation with IL-12 and IL-18 compared to normal SB CCR9+ T cells.  TL1A (a newly discovered TNF-like cytokine) in addition to IL-12/IL-18 further enhanced IFN-γ production by CCR9+ LP T cells from CD compared to normal SB CCR9+ T cells.  Further analysis of the TCRVβ repertoire in PBL in CD revealed the preferential usage of certain TCRVβ families among CCR9+ T cells compared to healthy volunteers.

Based on these data, we conclude that CCR9+ T cells in both MLN and PB show an activated phenotype in SB CD and an oligoclonal expansion.  In addition, they exhibit a predominant Th1 cytokine profile in response to polyclonal or cytokine stimulation with IL-12 and IL-18.  Since CCR9+ T cells appear to have a pro-inflammatory cytokine profile, the use of selective small molecule CCR9 inhibitors could represent a novel treatment for SB CD.     

aPrincipal Investigator