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Co-stimulation via CD28 induces activation of a refractory subset of MRL-Ipr/Ipr T lymphocytes
Authors:Clements, James L.   Winslow, Genine   Donahue, Christopher   Cooper, Sheldon M.   Allison, James P.   Budd, Ralph C.
Affiliation: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
Abstract:Peripheral lymphoid tissues of Ipr mice contain a large proportionof TCR{alpha}ß/CD3+CD4CD8 T cells that lacksurface CD2 and express the B cell isoform of CD45, B220. Thissubset of T cells does not proliferate or produce IL-2 in responseto mitogenic signals or TCR–CD3 ligation. At the sametime, these abnormal T cells display several characteristicsof an activated phenotype. Collectively, these properties ofIpr CD4CD8 T cells have functional parallels withanergic T cells. A critical co-stimulatory molecule implicatedin the prevention of or recovery from anergy is CD28, whichbinds the ligand BB1/B7 on certain accessory cells. Ipr CD4CD8T cells express normal levels of CD28 which is capable of transducinga strong proliferative signal to these cells in co-stimulationwith mitogens. However, proliferation of Ipr CD4CD8T cells in response to CD28 co-stimulation does not reach thelevels observed in normal T cells stimulated under similar conditions.Stimulation with anti-CD28 mAb in conjunction with phorbol myristateacetate and lonomycin promotes cell cycling in the CD2subset of CD4CD8 T cells, and results in a slightinduction of CD2 levels during the course of the culture period.However, the majority of cells obtained at the end of the cultureperiod remain TCR{alpha}ß+ CD4CD8, CD2low/–and B220high, similar to freshly isolated CD4CD8Ipr T cells. In contrast, if IL-2 is included in the cultures,a strong shift toward a CD2+ phenotype is observed by a majorityof the Ipr T cells. Upon repeat stimulation, these Ipr CD4CD8T cells can now proliferate in an IL-2-dependent manner whenstimulated with only anti-CD3 mAb or mitogens, in the absenceof exogenous IL-2 or anti-CD28 mAb. These data show that thehyporesponsiveness of Ipr CD4CD8 T cells doesnot result from a lack of CD28 expression, that it is not afixed state, and that it can be reversed by the induction ofcell cycling in the presence of IL-2. These observations extendthe parallels between Ipr CD4CD8 T cells and anergicT cells.
Keywords:CD2   IL-2   T cell anergy   T cell activation
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