Co-stimulation via cd28 induces activation of a refractory subset of mrl-ipr/lpr t lymphocytes

Peripheral lymphoid tissues of Ipr mice contain a large proportion of TCRa/3/CD3+CD4ܲCD8ܲ 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 CD4ܲCD8ܲ 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 CD4ܲCD8ܲ T cells express normal levels of CD28 which Is capable of transducing a strong proliferative signal to these cells In co-stlmulatlon with mitogens. However, proliferation of Ipr CD4ܲCD8ܲ T cells In response to CD28 co-stlmulatlon does not reach the levels observed In normal T cells stimulated under similar conditions. Stimulation with antl-CD28 mAb In conjunction with phorbol myristate acetate and lonomycln promotes cell cycling In the CD2ܲ subset of CD4ܲCD8ܲ 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 TCRa/3+ CD4ܲCD8ܲ, CD2taw/ܲ and B220hBBh, similar to freshly Isolated CD4ܲCD8ܲ 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 CD4ܲCD8ܲ T cells can now proliferate In an IL-2-dependent manner when stimulated with only antl-CD3 mAb or mitogens, in the absence of exogenous IL-2 or antl-CD28 mAb. These data show that the hyporesponslveness of Ipr CD4ܲCD8ܲ 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 CD4ܲCD8ܲ T cells and anergic T cells.