Identification of a bone marrow-derived CD8αα+ dendritic cell-like population in inflamed autoimmune target tissue with capability of inducing T cell apoptosis

Abstract

DCs play critical roles in promotion of autoimmunity or immune tolerance as potent APCs. In our anti-GBM GN model, WKY rats develop severe T cell-mediated glomerular inflammation followed by fibrosis. A DC-like cell population (CD8αα(+)CD11c(+)MHC-II(+)ED1(-)) was identified in the inflamed glomeruli. Chimera experiments demonstrated that the CD8αα(+) cells were derived from BM. The CD8αα(+) cells infiltrated glomeruli at a late stage (Days 28-35), coincident with a rapid decline in glomerular inflammation before fibrosis. The CD8αα(+) cells isolated from inflamed glomeruli were able to migrate rapidly from the bloodstream into inflamed glomeruli but not into normal glomeruli, suggesting that the migration was triggered by local inflammation. Despite high-level expression of surface and cellular MHC class II molecules, in vitro experiments showed that this CD8αα(+) DC-like cell induced apoptosis but not proliferation in antigen-specific CD4(+) T cells from T cell lines or freshly isolated from lymph nodes; they were not able to do so in the absence of antigens, suggesting induction of apoptosis was antigen-specific. Furthermore, apoptotic T cells were detected in a large number in the glomeruli at Day 32, coincident with the infiltration of the cells into glomeruli, suggesting that the cells may also induce T cell apoptosis in vivo. A potential role of this CD8αα(+) DC-like population in peripheral immune tolerance and/or termination of autoimmune inflammation was discussed.

Dendritic Cells: Two-Edged Swords in Pathogenesis of Autoimmune Glomerulonephritis

“…Indeed, a few studies, including one from our group, suggest the existence of such DC-mediated tolerance mechanisms. As we mentioned before, our group reported a new type of DC with a phenotype of CD8αα + CD11b/c + MHC-II + ED1 -OX62 -in our rat model for anti-GBM glomerulonephritis (55). This DC is not residential, but rather is selectively recruited into inflamed glomeruli.…”

“…This type of tDC has not been characterized well, and further investigation is needed. Our group is currently characterizing a new type of DC, which may be tolerogenic (55). The common features for the above DC-mediated tolerance mechanisms can be summarized as follows: 1) DCs act on naïve T cells, and 2) DCs induce tolerance in lymphoid tissues but not in peripheral tissues.…”

“…A novel DCmediated mechanism has been recently described in a rat anti-GBM glomerulonephritis model. Unlike many other types of DCs, this DC actively infiltrates inflamed autoimmune target tissues and presents the self antigen locally (55). The DC selectively induces apoptosis in the infiltrating self reactive pathogenic T cells, which recognize the presented self antigen.…”

Immunotherapy using lipopolysaccharide-stimulated bone marrow-derived dendritic cells to treat experimental autoimmune encephalomyelitis

“…+ T cells and inhibit CD4 + T cell-mediated inflammatory responses [26]. LPS treatment increases the number of CD11c +…”

Natural Recovery from Antiglomerular Basement Membrane Glomerulonephritis Is Associated with Glomeruli-Infiltrating CD8α+CD11c+MHC Class II+ Cells

“…As mimicking this naturally occurring recovery mechanism may lead to an antigen-specific immunotherapeutic strategy for treating autoimmune diseases, we explored this recovery mechanism. Although glomerular CD8+ T cells have been described, we have previously identified a novel CD8αα + CD11c + MHC II + DC-like myeloid cell population among glomeruli-infiltrating leukocytes (GIL) at transient stage from inflammation to fibrosis in WKY rats [20,21]. This cell, designated as GIL CD8α + cells, is able to induce antigen-dependent T cell apoptosis in vitro.…”