Co-stimulation via CD28 induces activation of a refractory subset of MRL-lpr/lpr T lymphocytes

Int Immunol. 1993 Nov;5(11):1451-60. doi: 10.1093/intimm/5.11.1451.

Abstract

Peripheral lymphoid tissues of lpr mice contain a large proportion of TCR alpha beta/CD3+CD4-CD8- T cells that lack surface CD2 and express the B cell isoform of CD45, B220. This subset of T cells does not proliferate or produce IL-2 in response to mitogenic signals or TCR-CD3 ligation. At the same time, these abnormal T cells display several characteristics of an activated phenotype. Collectively, these properties of lpr CD4-CD8- T cells have functional parallels with anergic T cells. A critical co-stimulatory molecule implicated in the prevention of or recovery from anergy is CD28, which binds the ligand BB1/B7 on certain accessory cells. lpr CD4-CD8- T cells express normal levels of CD28 which is capable of transducing a strong proliferative signal to these cells in co-stimulation with mitogens. However, proliferation of lpr CD4-CD8- T cells in response to CD28 co-stimulation does not reach the levels observed in normal T cells stimulated under similar conditions. Stimulation with anti-CD28 mAb in conjunction with phorbol myristate acetate and ionomycin promotes cell cycling in the CD2- subset of CD4-CD8- T cells, and results in a slight induction of CD2 levels during the course of the culture period. However, the majority of cells obtained at the end of the culture period remain TCR alpha beta+ CD4-CD8-, CD2low/- and B220high, similar to freshly isolated CD4-CD8- lpr T cells. In contrast, if IL-2 is included in the cultures, a strong shift toward a CD2+ phenotype is observed by a majority of the lpr T cells. Upon repeat stimulation, these lpr CD4-CD8- T cells can now proliferate in an IL-2-dependent manner when stimulated with only anti-CD3 mAb or mitogens, in the absence of exogenous IL-2 or anti-CD28 mAb. These data show that the hyporesponsiveness of lpr CD4-CD8- T cells does not result from a lack of CD28 expression, that it is not a fixed state, and that it can be reversed by the induction of cell cycling in the presence of IL-2. These observations extend the parallels between lpr CD4-CD8- T cells and anergic T cells.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • CD2 Antigens
  • CD28 Antigens / physiology*
  • Cells, Cultured
  • Clonal Anergy
  • Flow Cytometry
  • Interleukin-2 / physiology
  • Ionomycin / pharmacology
  • Lymphocyte Activation / genetics*
  • Lymphoproliferative Disorders / genetics
  • Mice
  • Mice, Inbred Strains
  • Receptors, Antigen, T-Cell, alpha-beta / physiology
  • Receptors, Immunologic / metabolism
  • T-Lymphocytes / cytology*
  • Tetradecanoylphorbol Acetate / pharmacology

Substances

  • Antibodies, Monoclonal
  • Antigens, Differentiation, T-Lymphocyte
  • CD2 Antigens
  • CD28 Antigens
  • Interleukin-2
  • Receptors, Antigen, T-Cell, alpha-beta
  • Receptors, Immunologic
  • Ionomycin
  • Tetradecanoylphorbol Acetate