CD4+CD25high regulatory cells in human peripheral blood

J Immunol. 2001 Aug 1;167(3):1245-53. doi: 10.4049/jimmunol.167.3.1245.

Abstract

Thymectomy in mice on neonatal day 3 leads to the development of multiorgan autoimmune disease due to loss of a CD(+)CD25(+) T cell regulatory population in their peripheral lymphoid tissues. Here, we report the identification of a CD4(+) population of regulatory T cells in the circulation of humans expressing high levels of CD25 that exhibit in vitro characteristics identical with those of the CD4(+)CD25(+) regulatory cells isolated in mice. With TCR cross-linking, CD4(+)CD25(high) cells did not proliferate but instead totally inhibited proliferation and cytokine secretion by activated CD4(+)CD25(-) responder T cells in a contact-dependent manner. The CD4(+)CD25(high) regulatory T cells expressed high levels of CD45RO but not CD45RA, akin to the expression of CD45RB(low) on murine CD4(+)CD25(+) regulatory cells. Increasing the strength of signal by providing either costimulation with CD28 cross-linking or the addition of IL-2 to a maximal anti-CD3 stimulus resulted in a modest induction of proliferation and the loss of observable suppression in cocultures of CD4(+)CD25(high) regulatory cells and CD4(+)CD25(-) responder cells. Whereas higher ratios of CD4(+)CD25(high) T cells are required to suppress proliferation if the PD-L1 receptor is blocked, regulatory cell function is shown to persist in the absence of the PD-1/PD-L1 or CTLA-4/B7 pathway. Thus, regulatory CD4 T cells expressing high levels of the IL-2 receptor are present in humans, providing the opportunity to determine whether alterations of these populations of T cells are involved in the induction of human autoimmune disorders.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Abatacept
  • Antigens, CD
  • Antigens, Differentiation / physiology
  • B7-1 Antigen*
  • B7-H1 Antigen
  • Blood Proteins*
  • CD4 Antigens / biosynthesis*
  • CD4 Antigens / blood
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CTLA-4 Antigen
  • Cells, Cultured
  • Coculture Techniques
  • HLA-DR Antigens / biosynthesis
  • Humans
  • Immunoconjugates*
  • Immunosuppressive Agents / pharmacology
  • Interleukin-2 / antagonists & inhibitors
  • Interleukin-2 / genetics
  • Kinetics
  • Leukocyte Common Antigens / biosynthesis
  • Lymphocyte Activation
  • Lymphocyte Count
  • Membrane Glycoproteins
  • Peptides / physiology
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / metabolism
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Antigen, T-Cell / physiology
  • Receptors, Interleukin-2 / biosynthesis*
  • Receptors, Interleukin-2 / blood
  • Signal Transduction / immunology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • B7-1 Antigen
  • B7-H1 Antigen
  • Blood Proteins
  • CD274 protein, human
  • CD4 Antigens
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Ctla4 protein, mouse
  • HLA-DR Antigens
  • Immunoconjugates
  • Immunosuppressive Agents
  • Interleukin-2
  • Membrane Glycoproteins
  • Peptides
  • RNA, Messenger
  • Receptors, Antigen, T-Cell
  • Receptors, Interleukin-2
  • Abatacept
  • Leukocyte Common Antigens