Failure of humoral tolerance to red blood cell (RBC) antigens may lead to autoimmune hemolytic anemia (AIHA), a severe and sometimes fatal, disease. Previous studies have shown that although tolerance is robust in HOD mice, autoantibodies are generated upon adoptive transfer of OTII CD4 T cells, which are specific for an epitope contained within the HOD antigen. These data imply that antigen presenting cells (APCs) are presenting RBC-derived autoantigen(s) and are capable of driving T cell activation. Given that multiple APCs participate in erythrophagocytosis, we utilized a transgenic approach to determine which cellular subsets were required for autoantigen presentation and subsequent autoreactive T cell activation.
HOD mice, which express an RBC-specific antigen consisting of hen egg lysozyme, ovalbumin, and human blood group molecule Duffy, were bred with IAb and Cre-expressing transgenic animals to generate mice that lack I-A expression on particular cell subsets. OTII CD4 T cell proliferation was assessed in vivo in HOD I-Ab xCre mice and in vitro upon co-culture with sorted APCs.
Analysis of HOD I-Ab xCre mice demonstrated that splenic conventional DCs, but not macrophages or monocytes, were required for autoantigen presentation to OTII CD4 T cells. Subsequent in vitro co-culture experiments revealed that both CD8 and CD8 dendritic cell (DC) subsets participate in erythrophagocytosis, present RBC-derived autoantigen, and stimulate autoreactive T cell proliferation.
These data suggest that if erythrocyte T cell tolerance fails, DCs are capable of initiating autoimmune responses. As such, targeting DCs may be a fruitful strategy for AIHA therapies.

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