CD69+ CD4+ CD25- T cells, a new subset of regulatory T cells, suppress T cell proliferation through membrane-bound TGF-beta 1

J Immunol. 2009 Jan 1;182(1):111-20. doi: 10.4049/jimmunol.182.1.111.

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-beta1, IL-2, and IFN-gamma. 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-beta1 can block their suppressive activity. We found that CD69(+)CD4(+)CD25(-) T cells express membrane-bound TGF-beta1, which mediates suppression of T cell proliferation. Furthermore, engagement of CD69 maintains high expression of membrane-bound TGF-beta1 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-beta1. Our data contribute to the better understanding of mechanisms for tumor immune escape.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / biosynthesis*
  • Antigens, CD / physiology
  • Antigens, Differentiation, T-Lymphocyte / biosynthesis*
  • Antigens, Differentiation, T-Lymphocyte / physiology
  • CD4 Antigens / biosynthesis*
  • Carcinoma, Lewis Lung / enzymology
  • Carcinoma, Lewis Lung / immunology
  • Carcinoma, Lewis Lung / pathology
  • Cell Line, Tumor
  • Coculture Techniques
  • Disease Progression
  • Enzyme Activation / immunology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Growth Inhibitors / physiology*
  • Interleukin-2 Receptor alpha Subunit* / metabolism
  • Lectins, C-Type
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / immunology
  • Lung Neoplasms / pathology
  • Melanoma, Experimental / enzymology
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / pathology
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Protein Binding / immunology
  • T-Lymphocyte Subsets / enzymology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / pathology
  • T-Lymphocytes, Regulatory / enzymology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology
  • Transforming Growth Factor beta1 / physiology*

Substances

  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD4 Antigens
  • CD69 antigen
  • Growth Inhibitors
  • Interleukin-2 Receptor alpha Subunit
  • Lectins, C-Type
  • Membrane Proteins
  • Transforming Growth Factor beta1
  • Extracellular Signal-Regulated MAP Kinases