REVERSAL OF HYPORESPONSIVENESS IN LPR CD4(-)CD8(-) T-CELLS IS ACHIEVED BY INDUCTION OF CELL CYCLING AND NORMALIZATION OF CD2 AND P59(FYN) EXPRESSION

T cells freshly isolated from the peripheral lymph nodes of autoimmune MRL lpr/lpr (lpr) mice contain a large proportion of functionally non-mature T cell receptor (TcR)-alpha beta(+)CD3(+)CD2(-)CD4(-)CD8(-) T cells displaying the B cell isoform of CD45, B220. These cells are hyporesponsive as defined by minimal interleukin-2 (IL-2) production and proliferation in response to stimulation. However, increased levels of inositol phosphates and a rapid mobilization of Ca2+ do occur upon stimulation of the TcR/CD3 complex. Furthermore, lpr CD4(-)CD8(-) T cells contain high levels of transcripts for the src-family tyrosine kinase p59(fyn), and express a constitutively tyrosine-phosphorylated CD3-zeta chain. These features bear a certain resemblance to anergized T cells. These similarities are extended to show that culturing of lpr CD4(-)CD8(-) T cells in the presence of IL-2, in combination with phorbol 12-myristate 13-acetate and ionomycin initiates cell cycling and results in the gain of function; re-stimulation now yields IL-2-dependent proliferation in the absence of exogenous IL-2. In parallel with this gain in function, the population of cells obtained after 1 week in culture retains the TcR-alpha beta(+)CD4(-)CD8(-) phenotype, yet displays increased levels of CD2, decreased surface B220, and normal amounts of p59(fyn)-specific transcripts. These findings show that cell cycling is associated with the recovery of functional capabilities by lpr CD4(-)CD8(-) T cells and is closely allied with surface CD2 expression. Thus, the hyporesponsiveness of lpr T cells is not a fixed state.