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International Immunology, Vol. 5, No. 11, pp. 1451-1460,November 1993
© 1993 Japanese Society for Immunology

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

James L. Clements, Genine Winslow1, Christopher Donahue, Sheldon M. Cooper, James P. Allison1 and Ralph C. Budd

Rheumatology and Clinical Immunology Unit, The University of Vermont College of Medicine Burlington, VT 05405, USA
1 Cancer Research Laboratory, University of California Berkeley, CA 94720, USA

Correspondence to: Correspondence to: R. C. Budd

Peripheral lymphoid tissues of Ipr mice contain a large proportion of TCR{alpha}ß/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 Ipr 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. Ipr 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 Ipr 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 lonomycin 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}ß+ CD4–CD8–, CD2low/– and B220high, similar to freshly isolated CD4–CD8– Ipr 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 Ipr T cells. Upon repeat stimulation, these Ipr 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 Ipr 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 Ipr CD4–CD8– T cells and anergic T cells.

Keywords: CD2, IL-2, T cell anergy, T cell activation

Received 8 March 1993, accepted 13 August 1993.


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