Reduced levels of a regulatory DC subtype may be linked to the development of spontaneous autoimmune disease in aging CD48 deficient mice

Abstract

CD48 is a member of the CD2 superfamily of co-stimulatory molecules and has an important role in immune response regulation. Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease. Its genetic basis indicates that three regions on different chromosomes (SLE1, 2 and 3) are linked with susceptibility to the disease at different severities. A sub-region of SLE1 on chromosome one (SLE1b) includes members of the CD2 superfamily. We have previously found that aging CD48 deficient (−/−) C57BL/6 mice develop spontaneous autoimmune disease, indicated in elevated levels of dsDNA, IgG and IgM antibodies and of activation markers on CD4+ and CD8+ T cells. We found no difference in the levels of CD4+CD25+ T cells in both groups of mice. However, levels of CD11clowCD45rbhigh DCs, recently characterized as a regulatory DC subtype (rDC), were at least 2-times lower in the bone marrow and the spleens of CD48−/− compared to WT mice. After LPS stimulation, expression of costimulatory molecules, CD40 and DEC205 were upregulated on CD48−/− rDC in contrast to WT rDC where the expression remained low. In addition, OT-II- derived CD4+ T cell proliferated and produced higher levels of IFN-γ and IL-4 when cultured with OVA-pulsed CD48−/− rDC compared to those cultured with OVA-pulsed WT rDCs. Our results indicate that low levels of rDC may be responsible for impaired regulation of the immune response in CD48−/− mice.