CD69+CD4+CD25− T Cells, a New Subset of Regulatory T Cells, Suppress T Cell Proliferation through Membrane-Bound TGF-β1

Abstract

The underlying mechanisms of tumor-induced immune suppression need to be fully understood. Regulatory T (Treg) cells have been shown to play an important role in tumor immune escape. Until now, many subsets of Treg cells have been described that can suppress T cell response via different mechanisms. CD69 is generally regarded as one of the activating markers; however, recent studies show that CD69 may exert regulatory function in the immune response. In this study, we have identified tumor-induced CD69+CD4+CD25− T cells as a new subset of CD4+ Treg cells. CD69+CD4+CD25− T cells increase dramatically along tumor progression, with up to 40% of CD4+ T cells in the advanced tumor-bearing mice. Distinct from the previously described CD4+ Treg cell subsets, CD69+CD4+CD25− T cells express high CD122, but they do not express Foxp3 and secrete IL-10, TGF-β1, IL-2, and IFN-γ. CD69+CD4+CD25− T cells are hyporesponsive and can suppress CD4+ T cell proliferation in a cell-cell contact manner. Interestingly, the fixed CD69+CD4+CD25− T cells still have suppressive activity, and neutralizing Abs against TGF-β1 can block their suppressive activity. We found that CD69+CD4+CD25− T cells express membrane-bound TGF-β1, which mediates suppression of T cell proliferation. Furthermore, engagement of CD69 maintains high expression of membrane-bound TGF-β1 on CD69+CD4+CD25− T cells via ERK activation. Our results demonstrate that CD69+CD4+CD25− T cells act as a new subset of regulatory CD4+ T cells, with distinct characteristics of negative expression of Foxp3, no secretion of IL-10, but high expression of CD122 and membrane-bound TGF-β1. Our data contribute to the better understanding of mechanisms for tumor immune escape.

Cord-Blood-Derived Mesenchymal Stromal Cells Downmodulate CD4+T-Cell Activation by Inducing IL-10-Producing Th1 Cells

“…5C). This observation is particularly interesting due to the regulatory role recently attributed to cells expressing CD69 [38,39]. Nevertheless, this increase in CD69 expression was not restricted to T-cells coexpressing IFNg and IL-10, since it was also expressed in about 40% of CD4 + Foxp3 -…”

Immune signature of tumor infiltrating immune cells in renal cancer

“…Tumor-induced CD69C CD4CCD25neg T cells have been claimed to be a new subset of regulatory T cells, since they are not Foxp3C, but express membrane-bound TGF-1 and can suppress T cell proliferation in a cell-cell contact manner. 24 Therefore, CD69C T cells could play a major role in the transition from a renal tumor controlled by immune cells to a tumor which evades immune control. A high expression of CD69CCD25neg T cells was found in chronic pancreatitis as well as in pancreatic ductal adenocarcinoma (associated with nodal invasion and higher grading) and L1CAM/ CD171 expression of tumor cells reduced proliferation, diminished CD25 expression and elevated CD69 expression in effector T cells.…”

A B-1a cell subset induces Foxp3− T cells with regulatory activity through an IL-10-independent pathway

“…Next, to further characterize the Treg-of-B1a cells, we used a number of molecules reported to be associated with the functions of Treg cells. [22][23][24][25][26][27][28][29][30] We found that Treg-of-B1a cells expressed a series of surface molecules, including ICOS, PD-1, GITR, OX40, IL-10R and TNFR2 (Figure 3b). Among them, ICOS, GITR, IL-10R and PD-1 were expressed at higher levels Therefore, B-1a cells are the major IL-10-producing cell population present in the steady-state peritoneal cavity, and they spontaneously produce IL-10 without any stimulation.…”