Increase in activated CD8+ T lymphocytes expressing perforin and granzyme B correlates with disease activity in patients with systemic lupus erythematosus

Abstract

Objective. Cytotoxic T lymphocyte-mediated killing using granzyme B has recently been proposed to be a preferential and selective source of autoantigens in systemic autoimmune diseases, including systemic lupus erythematosus (SLE), while other reports have indicated that cytolytic activity in SLE patients was decreased. The aim of this study was to examine the phenotypic and functional status of the CD8؉ T cells in SLE patients.Methods. Phenotype analysis of CD8؉ T cells was carried out using flow cytometry. The cytotoxic potential of CD8؉ T cells and its consequences were examined in redirected-killing experiments. SLE patients with quiescent disease (n ‫؍‬ 41) were compared with SLE patients with active disease (n ‫؍‬ 20), normal individuals (n ‫؍‬ 36), and control patients with vasculitis (n ‫؍‬ 14). Cytotoxic CD8؉ T cell differentiation was examined by coculture with differentiated dendritic cells (DCs) in the presence of SLE patient sera.Results. Patients with disease flares were characterized by higher proportions of perforin-and/or granzyme B-positive lymphocytes with a differentiated effector phenotype (CCR7؊ and CD45RA؉). The frequency of these cells in peripheral blood correlated with clinical disease activity as assessed by the SLE Disease Activity Index. These cells generated high amounts of soluble nucleosomes as well as granzyme B-dependent unique autoantigen fragments. Finally, the activation of DCs with serum from a patient with active lupus induced granzyme B expression in CD8؉ T lymphocytes.Conclusion. DCs generated in the presence of sera from SLE patients with active disease could promote the differentiation of CD8؉ effector T lymphocytes that are fully functional and able to generate SLE autoantigens. Our data disclose a new and pivotal role of activated CD8؉ T lymphocytes in SLE pathogenesis.

Predominance of CD8+ T lymphocytes among periglomerular infiltrating cells and link to the prognosis of class III and class IV lupus nephritis

“…We have reported that dendritic cells derived from normal monocytes cultured with SLE sera or IFN␣ had the unique capacity to stimulate CD8ϩ T lymphocytes and to skew their phenotype toward cytotoxic effector cells (11). Consistent with this observation, Peterson et al (29) found that renal glomeruli from patients with lupus nephritis were characterized by high expression of genes with promoters containing type I IFN response elements.…”

“…We demonstrated that this T lymphocyte subset activation was mainly type I IFN-dependent and that these cells were able to produce large amounts of nuclear-containing bodies in vitro (11). Even though the increase in this cell population was correlated with disease activity, data are still lacking for their direct involvement in tissue damage.…”

“…We recently reported that increased CD8ϩ cytotoxic T lymphocytes are characteristically present in the peripheral blood of SLE patients (11). We demonstrated that this T lymphocyte subset activation was mainly type I IFN-dependent and that these cells were able to produce large amounts of nuclear-containing bodies in vitro (11).…”

“…The correlation between the percentages of activated CD8ϩ T cells in the peripheral blood and the total number of renal CD8ϩ cells suggests that they are linked and are the tangible witness of the ongoing cellular autoimmune response. The implication of CD8ϩ T cells in glomerular injury, while still elusive, could involve and be associated with other disease features that have already been described, such as 1) the secretion of inflammatory cytokines, including IFN␥ and tumor necrosis factor ␣ (30); 2) a cytotoxic pathway against glomerular autoantigens that may promote the in situ generation of nuclear-containing bodies and the secondary deposition of immune complexes (11); and 3) a direct cooperation with B cells to produce immunoglobulins, since it has been demonstrated that the expression of B cell genes by glomeruli paralleled the extent of periglomerular infiltration by CD3ϩ T cells on renal histology sections (29). The specific localization of CD8ϩ T cell infiltrates within the periglomerular area and their correlation with degradation of glomerular function strongly support a direct role in glomerular injury.…”

“…In vitro studies also demonstrated that SLE dendritic cells have the unique capacity to activate CD8ϩ T lymphocytes, promoting their differentiation into effector-type cytotoxic T lymphocytes (11), whereas in vivo, there was an increased proportion of cytotoxic T lymphocytes, which correlated with scores on the SLE Disease Activity Index (SLEDAI) (12,13). Interestingly, type I IFN receptor-knockout lupus mice are characterized by a decreased activation of their CD8ϩ T cell subset (14).…”