ABNORMAL SIGNAL-TRANSDUCTION THROUGH CD4 LEADS TO ALTERED TYROSINE PHOSPHORYLATION IN T-CELLS DERIVED FROM MRL-LPR LPR MICE/

CD4+ T cells play a crucial role in the development of lupus in MRL-lp r/lpr mice: incomplete deletion/silencing of self-reactive CD4+ T cell s leads to T cell activation, which causes both polyclonal B cell acti vation and T cell infiltration of multiple organs. Furthermore, anti-C D4 antibody therapy ameliorates disease and prolongs survival, Because CD4 is normally involved in both tolerance induction and T cell activ ation, we questioned whether signaling through CD4 was normal among T cells in this strain. For this purpose, signal transduction in CD4+ T cells derived from MRL-lpr/lpr and normal mice were compared, using an autoreactive CD4+ T cell clone and freshly isolated CD4+ T cells deri ved from mice of varying ages. Tyrosine phosphorylation was similar am ong MRL and normal CD4+ T cells after cross-linking with either anti-T CR antibody or anti-CD3 antibody, and following co-culture with Con A. In constrast, cross-linking of surface CD4 resulted in deficient tyro sine phosphorylation of cellular proteins in MRL T cells. By compariso n, lck protein expression in MRL CD4+ T cells was found to be lower th an normal. However, following stimulation with Con A, Eck enzyme activ ity, as detected by autophosphorylation of lck, was comparable in MRL and normal T cells. The observed differences were present in the autor eactive T cell clone as well as in T cells isolated from both pre-dise ased and diseased mice, and they could not be explained by variation i n surface density of CD4. These results raise the possibility that abn ormal signaling through CD4 may contribute to impaired tolerance and e xpansion of autoreactive T cells exhibited in MRL-lpr/lpr mice.