3rd Annual BMRP Investigator Meeting - Abstract

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

Daocheng Zhu, Armine Avanesyan and Konstantinos A. Papadakisa

Division of Gastroenterology and 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).  CCR9+ T cells isolated from the peripheral blood (PB) of normal donors have characteristics of circulating mucosal T cells, since they respond to CD2 stimulation and produce large amounts of IFN-γ and IL-10.  In addition, the frequency of CCR9+ T lymphocytes is increased in the circulation of patients with SB Crohn’s disease (CD) and celiac disease implicating this T cell subset in the pathogenesis of SB-immune mediated diseases.

In this report, we have characterized the phenotype and cytokine profile of CCR9+ T lymphocytes in SB 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, e.g., OX-40, CD40L and HLA-DR expression.  Interestingly, we found no difference in the phenotype of CCR9+ T cells in inflamed versus normal SB lamina propria lymphocytes (LPL) where expression of activation markers, other than CD69, was low compared to draining MLN.  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.  Interestingly, CCR9+ peripheral blood and mucosal CCR9+ T cells show an enhanced production of IFN-γ in response to cytokine stimulation with IL-12 and IL-18.  The addition of TL1A (a newly discovered TNF-like cytokine) to cytokine stimulation enhanced IFN-g production by CCR9+ LP T cells by 37- to 105-fold.

Based on these data, we conclude that CCR9+ T cells in both MLN and PB show an activated phenotype in SB CD.  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