Reversal of hyporesponsiveness inlpr CD4−CD8− T cells is achieved by induction of cell cycling and normalization of CD2 and p59fyn expression

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Abstract
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)-αβ+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 p59fyn, and express a constitutively tyrosine-phosphorylated CD3-ζ 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-αβ+CD4−CD8− phenotype, yet displays increased levels of CD2, decreased surface B220, and normal amounts of p59fyn-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.