This type of evolution also facilitates a mechanism for qualitatively changing a receptor's signaling potential. A number of type I transmembrane IgSF members including CEACAMs and KIRs are composed of an amino-terminal extracellular "environmental sensor" and a carboxy-terminal cytoplasmic tail which can contain either inhibitory (ITIM) or activating motifs (ITAM or a positively charged amino acid in the transmembrane region permitting coupling with activating adaptors such as DAP12 [42] ). Unequal crossing-over at such gene loci encompassing the corresponding exons could result, in a single step, in genes encoding receptors with a drastically changed signaling potential by combining the same extracellular domain with a cytoplasmic tail of opposite function. This allows rapid adaptation to environmental changes and the creation of so-called paired immune receptors. An example for such a mechanism is found for the KIR gene KIR3DL/S, where either an inhibitory variant or an activating variant encoding KIR gene is found in different human individuals at the same locus [43] . In addition, a change in the receptor's signaling potential which may be the result of an arms race between pathogens and the host immune system has been reported recently for mice. The murine cytomegalovirus (MCMV) induces in infected cells expression of the virus-encoded GPI-anchored m157 protein, which binds to the activating, DAP12-associating killer receptor Ly49H in MCMV-resistant mice leading to NKcell-mediated cytotoxicity. MCMV-susceptible mouse CEACAM1 and CEACAM28 genomic regions involved in gene conversion Figure 9 CEACAM1 and CEACAM28 genomic regions involved in gene conversion. The 2332 bp genomic region of CEACAM1 which covers nearly 1 kb of the 5'-flanking region (5'-FR), the leader exon (L), intron 1 (IntI), the N domain exon (N) and part of intron 2 (Int II) is highly conserved in CEACAM28 (99%) and, therefore, probably participated in a recent gene conversion event. The homologous sequences upstream and downstream from the conserved region are less conserved (80% and 92%, respectively) (A). This can also be deduced from the degree of conservation of the amino acid sequences encoded by the leader, N and A domains which is much less outside of the gene conversion region. Note that CEACAM28 contains two A2 type domains (B). [44] . It was suggested that the activating receptor gene was derived from the gene encoding the inhibitory receptor to counteract a virus that exploits the inhibitory receptor during infection and that this mechanism may apply to many other activating receptors that have inhibitory counterparts [45, 46] . However, recently it was shown for the human SIGLEC5 and SIGLEC14 genes that the direction of gene conversion that generates paired immune receptors is not always the same. This indicates that also other needs drive the evolution of paired receptors like the fine tuning of immune responses [45] . Host-pathogen interactions involving both proteins with ITIM or ITAM signaling motifs have also been reported for humans. The primate-specific CEACAM1-related protein CEACAM3 which contains an N domain closely related to that of CEACAM1 (88% amino acid sequence identity) and a cytoplasmic tail with an ITAM is exclusively expressed in granulocytes. Due to its close relatedness with the ITIM-bearing gonococcal receptor CEACAM1 it can act as decoy receptor for Neisserial pathogens and is able to induce clearance of gonococcal infections by granulocytes. Mutational analyses demonstrated that the cytoplasmic ITAM is instrumental for this process [24] .