Co-stimulation via CD28 induces activation of a refractory subset of MRL-lpr/lpr T lymphocytes.
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.
Clements
J L
JL
Rheumatology and Clinical Immunology Unit, University of Vermont College of Medicine, Burlington 05405.
Winslow
G
G
Donahue
C
C
Cooper
S M
SM
Allison
J P
JP
Budd
R C
RC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D018801:CD2 Antigens; D018106:CD28 Antigens / Q000502:physiology*; D002478:Cells, Cultured; D017635:Clonal Anergy; D005434:Flow Cytometry; D007376:Interleukin-2 / Q000502:physiology; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics*; D008232:Lymphoproliferative Disorders / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000502:physiology; D011971:Receptors, Immunologic / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D018801:CD2 Antigens; D018106:CD28 Antigens; D007376:Interleukin-2; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011971:Receptors, Immunologic; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate