Inflammatory regulatory T cells in the microenvironments of ulcerative colitis and colon carcinoma.
Foxp3(+)CD4(+) regulatory T (Treg) cells are thought to express negligible levels of effector cytokines, and inhibit immune responses and inflammation. Here, we have identified a population of IL-8(+)Foxp3(+)CD4(+) T cells in human peripheral blood, which is selectively increased in the microenvironments of ulcerative colitis and colon carcinoma. Phenotypically, this population is minimally overlapping with IL-17(+)Foxp3(+)CD4(+) T cells, and is different from IL-8(-)Foxp3(+)CD4(+) T cells in the same microenvironment. 40-60% of IL-8(+)Foxp3(+)CD4(+) T cells exhibit naive phenotype and express CD127, whereas IL-8(-)Foxp3(+)CD4(+) cells are basically memory T cells and express minimal CD127. The levels of CXCR5 expression are higher in IL-8(+)Foxp3(+) cells than in IL-8(-)Foxp3(+) cells. IL-2 and TGFβ induce IL-8(+)Foxp3(+) T cells. Exogenous Foxp3 expression promotes IL-8(+)Foxp3(+) T cells and inhibits effector cytokine IFNγ and IL-2 expression. Furthermore, Foxp3 binds to IL-8 proximal promoter and increases its activity. Functionally, IL-8(+)Foxp3(+) T cells inhibit T cell proliferation and effector cytokine production, but stimulate inflammatory cytokine production in the colon tissues, and promote neutrophil trafficking through IL-8. Thus, IL-8(+)Foxp3(+) cells may be an "inflammatory" Treg subset, and possess inflammatory and immunosuppressive dual biological activities. Given their dual roles and localization, these cells may be in a unique position to support tumor initiation and development in human chronic inflammatory environment.
Department of Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Ilona
I
Kryczek
Departments of Clinical Laboratory and Surgery, and Medical Research Center, Union Hospital, Huazhong University of Science and Technology School of Medicine , Wuhan, China.
Lin
L
Wang
Department of Surgery, University of Michigan, Ann Arbor, MI, USA; Departments of Clinical Laboratory and Surgery, and Medical Research Center, Union Hospital, Huazhong University of Science and Technology School of Medicine, Wuhan, China.
Ke
K
Wu
Department of Surgery, University of Michigan, Ann Arbor, MI, USA; Departments of Clinical Laboratory and Surgery, and Medical Research Center, Union Hospital, Huazhong University of Science and Technology School of Medicine, Wuhan, China.
Wei
W
Li
Department of Surgery, University of Michigan, Ann Arbor, MI, USA; Departments of Clinical Laboratory and Surgery, and Medical Research Center, Union Hospital, Huazhong University of Science and Technology School of Medicine, Wuhan, China.
Ende
E
Zhao
Department of Surgery, University of Michigan , Ann Arbor, MI, USA.
Tracy
T
Cui
Department of Surgery, University of Michigan , Ann Arbor, MI, USA.
Shuang
S
Wei
Department of Surgery, University of Michigan , Ann Arbor, MI, USA.
Yan
Y
Liu
Department of Surgery, University of Michigan , Ann Arbor, MI, USA.
Yin
Y
Wang
Department of Surgery, University of Michigan , Ann Arbor, MI, USA.
Linda
L
Vatan
Department of Surgery, University of Michigan , Ann Arbor, MI, USA.
Wojciech
W
Szeliga
Department of Pathology, University of Michigan , Ann Arbor, MI, USA.
Joel K
JK
Greenson
Department of Clinical Immunology, Medical University of Lublin, Lublin, Poland; 2nd Department of General Surgery, Medical University of Lublin, Lublin, Poland.
Jacek
J
Roliński
2nd Department of General Surgery, Medical University of Lublin , Lublin, Poland.
Witold
W
Zgodzinski
Department of Colorectal Surgery, Cleveland Clinic, Western Reserve University , Cleveland, Ohio, USA.
Emina
E
Huang
Departments of Clinical Laboratory and Surgery, and Medical Research Center, Union Hospital, Huazhong University of Science and Technology School of Medicine , Wuhan, China.
Kaixiong
K
Tao
Departments of Clinical Laboratory and Surgery, and Medical Research Center, Union Hospital, Huazhong University of Science and Technology School of Medicine , Wuhan, China.
Guobin
G
Wang
Department of Surgery, University of Michigan , Ann Arbor, MI, USA.
Weiping
W
Zou
Colon carcinoma; IL-17; IL-8; Regulatory T cell; Th17; neutrophil; tumor immunity; ulcerative colitis