Environmental factors determine DAP 12 deficiency to either enhance or suppress immunopathogenic processes

DNAX‐activation protein 12 ( DAP 12), a transmembrane adapter, plays a major role in transducing activation signals in natural killer cells and various myeloid cells. Quantitative RT ‐ PCR detected in normal mouse eyes considerable levels of DAP 12 and multiple DAP 12‐coupled receptors, in particular TREM ‐1, C lec5a and SIRP b1. The role of DAP 12 and its receptors in experimental autoimmune diseases has been controversial. Here, we analysed the effect of DAP 12 deficiency on the capacity of mice to mount immunopathogenic cellular responses to the uveitogenic ocular antigen and interphotoreceptor retinoid‐binding protein ( IRBP ), and to develop experimental autoimmune uveitis ( EAU ). Surprisingly, sequential analysis of EAU in mice deficient in DAP 12 in two different animal facilities at first revealed enhanced disease as compared with wild‐type mice, but when these mice were re‐derived into a second, cleaner, animal facility, the response of control mice was essentially unchanged, whereas the DAP 12 null mice were markedly hyporesponsive relative to controls in the new facility. Accordingly, when stimulated in vitro with IRBP , lymphocytes from the DAP 12‐deficient mice housed in the two facilities proliferated and produced opposite profiles of pro‐inflammatory and anti‐inflammatory cytokines, compared with their controls. These findings therefore demonstrate that the effects of DAP 12 deficiency on development of autoimmune disease are dramatically affected by environmental factors.