Tim-3 expression defines regulatory T cells in human tumors

PLoS One. 2013;8(3):e58006. doi: 10.1371/journal.pone.0058006. Epub 2013 Mar 5.

Abstract

Tim-3, a member of the novel Tim (T cell immunoglobulin and mucin domain) family, has been reported to negatively regulate the immune responses against viral infection and had implications for autoimmune disease. However, the nature and role of Tim-3(+) CD4 T cells in human tumors remain largely unknown. In the present study, we characterized Tim-3(+) CD4 T cells in 100 specimens from human hepatocellular, cervical, colorectal and ovarian carcinoma patients. Compared with peripheral blood and nontumor-infiltrating lymphocytes, the lymphocytes isolated from the corresponding tumor tissues of hepatocellular, cervical, colorectal and ovarian carcinoma patients contained significantly greater proportion of Tim-3(+) CD4 T cells. The majority of tumor-derived Tim-3(+) CD4 T cells exhibited an impaired capacity to produce IFN-γ and IL-2, but expressed higher levels of CD25, Foxp3, CTLA-4 and GITR than their Tim-3(-) CD4 T cell counterparts. In contrast, most Tim-3(+) CD4 T cells isolated from the paired nontumor tissues and peripheral blood did not express these molecules. Moreover, tumor-derived Tim-3(+) CD4 T cells, but not tumor-derived Tim-3(-) CD4 T cells, significantly suppressed the proliferation of autologous CD8(+) T cells in vitro. Notably, multi-color immunofluorescence and confocal microscopy demonstrated that Tim-3(+)Foxp3(+)CD4(+) cells were preferentially distributed in the tumor nest rather than the peritumoral stroma of hepatocellular carcinoma. Together, our data indicate that Tim-3-expressing CD4 T cells in human tumors could represent the functional regulatory T cells which contribute to the formation of the immune-suppressive tumor micromilieu.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Hepatocellular / immunology
  • Colorectal Neoplasms / immunology
  • Female
  • Galectins / immunology
  • Hepatitis A Virus Cellular Receptor 2
  • Humans
  • Immune Tolerance
  • Interferon-gamma / biosynthesis
  • Interleukin-2 / biosynthesis
  • Liver Neoplasms / immunology
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Male
  • Membrane Proteins / immunology*
  • Middle Aged
  • Neoplasms / immunology*
  • Ovarian Neoplasms / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • Tumor Microenvironment / immunology
  • Uterine Cervical Neoplasms / immunology
  • Young Adult

Substances

  • Galectins
  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • IL2 protein, human
  • Interleukin-2
  • LGALS9 protein, human
  • Membrane Proteins
  • Interferon-gamma

Grant support

This work was supported by project grants from the National Basic Research Program of China (2010CB529904 and 2011CB811305; http://www.973.gov.cn/Default_3.aspx), the National Natural Science Foundation of China (81230073 and 91029737; http://www.nsfc.gov.cn/Portal0/default152.htm), and the Ministry of Health of China (2012ZX10002-011; http://www.moh.gov.cn/publicfiles//business/htmlfiles/wsb/index.htm). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.