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.
Highlights
Tim-3, a member of the novel T cell immunoglobulin and mucin domain (Tim) family, was originally identified as a negative immune regulator which is expressed on T helper 1 (Th1) cells, but not Th2 cells [1]
To explore the potential role of Tim-3 in tumor immunopathology, we first examined the distribution of Tim-3 in lymphocytes freshly isolated from the paired tumor and nontumor tissues of 46 hepatocellular carcinoma (HCC) patients, as well as lymphocytes isolated from the peripheral blood of 31 HCC patients and 36 healthy donors
With respect to CD4 T cells, Tim-3 was only expressed on a small fraction of the circulating CD4 T cells in healthy individuals, with slightly higher levels of circulating Tim-3+ CD4 T cells observed in HCC patients (Figure 1A and 1B)
Summary
Tim-3, a member of the novel T cell immunoglobulin and mucin domain (Tim) family, was originally identified as a negative immune regulator which is expressed on T helper 1 (Th1) cells, but not Th2 cells [1]. Growing evidence indicates that Tim-3 is expressed on multiple cell types [5,6] and is involved in the pathogenesis of autoimmune disease and virus infection [7]. Upregulation of Tim-3 expression has been observed on exhausted CD8 T cells isolated from patients infected with human immunodeficiency virus (HIV), Hepatitis B virus (HBV), Hepatitis C virus (HCV) and Herpes simplex virus (HSV), and correlated with inefficient antiviral activity [9,10,11,12,13]. Tim expression on Foxp3+ Tregs was found in mouse skin transplantation model and chronic HCV-infected patients [14,15]. Such dysregulation of Tim-3 expression in disease settings indicates that Tim-3 may play an important role in adaptive immune responses
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have