Functional Th1 cells are required for surgical adhesion formation in a murine model.
Tissue trauma in the peritoneal and pelvic cavities following surgery or bacterial infection results in adhesions that are a debilitating cause of intestinal obstruction, chronic pelvic pain, and infertility in women. We recently demonstrated that CD4(+) alphabeta T cells are essential for development of this process. Using a murine model of experimental adhesion formation, we now demonstrate that adhesion formation is characterized by the selective recruitment of Tim-3(+), CCR5(+), CXCR3(+), IFN-gamma(+) cells, indicating the presence of a Th1 phenotype. We further demonstrate that adhesion formation is critically dependent on the function of Th1 cells because mice genetically deficient for IFN-gamma, T-bet, or treated with Abs to the Th1-selective chemoattractant IL-16 show significantly less adhesion formation than wild-type mice. In addition, disrupting the interaction of the Th1-specific regulatory molecule Tim-3, with its ligand, significantly exacerbates adhesion formation. This enhanced response is associated with increases in the level of neutrophil-attracting chemokines KC and MIP-2, known to play a role in adhesiogenesis. These data demonstrate that the CD4(+) T cells orchestrating adhesion formation are of the Th1 phenotype and delineate the central role of T-bet, Tim-3, IFN-gamma, and IL-16 in mediating this pathogenic tissue response.
Tzianabos
Arthur O
AO
Department of Medicine and Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
Holsti
Matthew A
MA
Department of Medicine and Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
Zheng
Xin-Xiao
XX
Division of Immunology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115.
Stucchi
Arthur F
AF
Department of Surgery, Boston University Medical Center, Boston, MA 02118.
Kuchroo
Vijay K
VK
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
Strom
Terry B
TB
Division of Immunology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115.
Glimcher
Laurie H
LH
Harvard School of Public Health and Harvard Medical School, Boston, MA 02115.
Cruikshank
William W
WW
Pulmonary Center, Boston University School of Medicine, Boston, MA 02118.
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D000072597:Hepatitis A Virus Cellular Receptor 2; D007371:Interferon-gamma / Q000378:metabolism; D019410:Interleukin-16 / Q000378:metabolism; D051379:Mice; D011183:Postoperative Complications; D011991:Receptors, Virus / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*; D000267:Tissue Adhesions / Q000276:immunology* / Q000473:pathology*; D000098815:T-bet Transcription Factor
D016207:Cytokines; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D019410:Interleukin-16; D011991:Receptors, Virus; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma