The immune system responds to antigens that engage specialized receptors present on the T cell surface (TCR) (Yablonski and Weiss, 2001). This engagement induces various intracellular biochemical interactions that culminate in the transmis sion of an extracellular signal that can trigger cell activation, proliferation, secretion of soluble mediators, phenotypic changes, acquisition of effector functions, anergy, and programmed cell death (Lanzavecchia et al., 1999; Germain, 2001; Yablonski and Weiss, 2001). The TCR stimulation outcome can vary considerably depending on the degree and extent of integration of other membrane receptor-initiated specific accessory signals. In particular, CD28-CD80/86 and CD40-CD40 ligand interactions are important for complete T cell and B cell activation, respectively. Because TCR-mediated signaling events direct these diverse but equally important outcomes, it is likely that the diverse cellular aberrations described in lupus patients reflect signaling defect(s) responsible for the disease pathogenesis. Such defects might be due to expression of a signaling molecule(s) stemming from either a defective gene(s) or defective gene expression regulation.
Tsokos et al. studied TCR/CD3-mediated signaling events to identify lupus T cell primary abnormalities (Vassilopoulos et al., 1995; Liossis et al., 1998). Using anti-human CD3 monoclonal antibody (mAb), they showed that lupus T cells exhibited significantly increased Ca2+ responses compared with the T cell responses from patients with non-SLE autoimmune disease (Vassilopoulos et al., 1995). In particular, anti-CD3 mAb enhanced Ca2+ fluxes in lupus but not in nonlupus T cell clones. Furthermore, they also demonstrated that lupus TCR/CD3 signaling is defective in tyrosine phosphorylation, which is necessary for proper T cell activation (Liossis et al., 1998). Specifically, T cell stimulation in SLE patients results in significantly enhanced production of tyrosine-phosphorylated cellular proteins and consists of an early elevated response as well as a steep decrease to baseline phos-phorylation levels. In contrast, protein tyrosine phosphorylation in normal T cells gradually increases during the same time period (Liossis et al., 1998). Taken together, these results suggest that proximal signaling by the TCR of lupus T cells is more sensitive in terms of peak intensity or TCR signaling duration, which would elicit abnormally high T cell activation that could cause tissue damage.
T cell activation is regulated by a number of cell surface and intracellular molecules as well as other cell types. Filaci et al. (2001) showed that the inhibitory function in CD8-positive cells in lupus patients is low, which would contribute to the development of lupus (Filaci et al., 2001). Recent suppressor T cell studies revealed that CD4+CD25+ T cells play a pivotal role in the development of autoimmune diseases in mice (Shevach et al., 2001). Several groups reported that human blood also possesses CD4+CD25+ T cells that have suppres-sive function (Sakaguchi, 2004). So far, the contribution of CD4+CD25+ T cells to lupus has not been reported, but much attention will be paid to the possible role of this unique population in the defective T cell response of lupus patients.
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