The arms race and immune diversification

diversification Host-pathogen interactions constitute a constant, long-term evolutionary arms race. This arms race is described as a competition between high rates of mutation and/or variation in microbes with short generation times versus long-lived hosts with corresponding low mutation rates (Haldane, 1949). This conflict is based on the relatively frequent appearance of new pathogen variants that may be more virulent, and thereby more successful and so could become established in the population. On the other side of the arms race, the host immune system must respond to pathogen variation within time scales that may be significantly shorter than host generation times. To survive, hosts employ a variety of mechanisms to diversify their immune response. Higher vertebrates use somatic recombination to generate large numbers of slightly variant immunoglobulin (Ig) family proteins that interact with pathogens (Neuberger, 2008). The alternative adaptive immune response that has recently been characterized in lampreys and hagfish has a unique mechanism that assembles variable lymphocyte receptor (VLR) genes from cassettes of gene segments encoding leucine-rich repeats (LRRs) (Nagawa et al., 2007; Rogozin et al., 2007). The VLR genes are expressed by two types of lamprey lymphocytes that resemble B and T cells (Guo et al., 2009). The level of diversity of the VLR genes generated by gene assembly has been estimated to be at least as great as that for the Ig family resulting from somatic recombination. The KIR genes – at the intersection of adaptive and innate immunity The major histocompatibility complex (MHC) gene family in higher vertebrates is composed of a number of closely clustered genes, each with multiple alleles. The diversity that is generated by multiple alleles at multiple loci is central to pathogen recognition and to the generation of specific immune responses. The regions of the MHC genes that have the highest levels of polymorphism are those that encode the peptide-binding groove and that are under selection for successful presentation of pathogen peptides to T-cell receptors (for reviews, see Vogel et al., 1999; Woelfing et al., 2009). The killer immunoglobulin-like receptors (KIR) are encoded by a highly diverse gene cluster, and function at the intersection of adaptive and innate immunity in vertebrates (Martinsohn et al., 1999; Biassoni, 2009). KIR proteins are expressed on natural killer (NK) cells and interact with MHC class I molecules encoded by a variety of the class I genes and alleles. Two types of KIR proteins are displayed on human NK cells: inhibitory KIR proteins that block the cytotoxic activity of NK cells, and activating KIR proteins that promote NK cell killing through association with adaptor signaling proteins. Inhibitory KIR proteins survey the level of MHC expression on self cells, which is a self-monitoring system where high levels indicate that the cell is normal and that cytotoxic activity of the NK cells is inhibited. Alternatively, virally infected cells have reduced levels of MHC expression to which NK cells respond cytotoxically. NK cells deploy an array of inhibitory and activating KIR proteins to regulate cytotoxic responses to self, altered self (virus infection) and pathogens (Biassoni, 2009). Diversity of the MHC genes is driven by pathogen pressure, and the diversity of the KIR genes is driven by the MHC diversity (Marinez-Borra and Khakoo, 2008). In humans, 15 to 17 KIR genes cluster in a head-to-tail orientation about 2 kb apart