Structural and Functional Heterogeneity in the CD200R Family of Immunoregulatory Molecules and their Expression at the Feto-maternal Interface
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PROBLEM: We have shown that CD200Fc, a chimeric molecule including the extracellular domain of CD200 and a murine immunoglobulin (Ig)G2a Fc region, regulates immune responses and prevents T helper (Th)1 cytokine-triggered spontaneous abortions in mice. CD200 is expressed on a subpopulation of uterine decidua cells and on trophoblast, both in the mouse and human. The receptor(s) for CD200, CD200R(s), was not previously well-characterized. METHODS: 5'-rapid amplification of cDNA ends (RACE), cDNA and genomic DNA clone analysis were used to identify a family of CD200Rs on mouse chromosome 16, juxtaposed to the CD200 gene, named CD200R1, R2, R3, and R4. Northern blot and reverse transcriptase polymerase chain reaction (RT-PCR) analysis was used to detect expression of different CD200R subtypes in different organs. Rabbit polyclonal and rat monoclonal antibodies (mAbs) to CD200R isoforms was used for fluorescence-activated cell sorter (FACS) analysis, to test for immunomodulatory effects on allogeneic mixed-lymphocyte responses in vitro, and for immunohistochemistry. RESULTS: The CD200Fc was able to interact physically with each of the CD200Rs expressed on the cell surface. Northern blot and RT-PCR analyses indicated distinct patterns of CD200R isoform mRNA expression in different tissues and FACS analyses confirmed unique cell- and tissue-specific expression of the different CD200Rs. mAbs directed against the different isoforms modified the development of in vitro alloimmune responses. The addition of anti-CD200R1/R4 elicited immunomodulatory responses in vitro comparable to findings with CD200Fc, but different from the effects of anti-CD200R2-3. CONCLUSIONS: These data provide evidence for a family of CD200R molecules in the mouse genome and defines the existence of previously unrecognized diversity in the CD200/CD200R immunomodulatory gene member family. Although this gene member family is clustered in the genome, the different CD200Rs and CD200 exhibit distinct expression patterns and functional properties. Restricted CD200R isoform expression at the feto-maternal interface suggests CD200:CD200R interactions may serve important function(s) determining the successful outcome of pregnancy.