Evolution of Immune System
The “Big Bang”, otherwise known as the Cambrian explosion, represents an evolutionary milestone, as it produced geological pressures and dramatically diversified several phyletic lineages that eventually gave rise to the vertebrates (Bayne, 2003). It is now generally appreciated that the ability to synthesize unique antigen-recognition receptors from germline encoded gene segments was acquired by two rounds of genome-wide duplications and genetic shifts (Suthler 1999), as well as the contribution of several environmental pressures in jawed vertebrates (cite several). In addition, an important biological and never-ending challenge came from the parallel evolution of pathogens, placing an important pressure on the hosts, which is consistently met by new form of immune components (Schmid-Hempel, 2009).
Therefore, the evolution of an adaptive immune system 500 million years ago, gave our vertebrate ancestors a survival advantage against the selective pressure of ecological and environmental events, as well as increasingly complex invading pathogens. The adaptive immune system is dependent upon functionality of the major histocompatibility complex (MHC) loci and combinatorial rearrangement of the T- and B-lymphocyte receptors, TCR and BCR respectively, for self vs. non-self recognition (Danchin 2003). The origins of the MHC and natural killer cell (NKC) receptors are not completely understood, but there is compelling evidence suggesting that the origins of the MHC region, which originally contained NKC receptors, gave rise to the vertebrate adaptive immune system. The genetic organization of the MHC can be traced back to ancient multicellular ancestors, such as Trichoplax adhaerens, originating in what is known as the “proto-MHC region” (Suurvali, 2014). Susumo Ohno (1970) first proposed that gene duplication and the presence of paralogue MHC genes allowed the development of new immune functions in vertebrates without disrupting previously acquired functions.
Suurvali et al. (2014) reported that the genetic homology of proto-MHC markers in placozoans and T. adhaerens indicates that the adaptive immune system evolved from a region functionally linked to stress responses, ubiquitination and protein catabolism. Indeed, the Salomonsen-Kaufman model (1999 and 2011) suggests that not only the “classical MHC genes” but also the associated antigen processing and peptide loading genes were present in the proto-MHC, indicative as to why those genes exhibit tight linkage disequilibrium to this day. This model has been supported by the discovery of genes with sequence homology to TAP and tapasin genes in primordial MHC regions of protochordates (Flajnik and Kashara 2010). In addition to MHC I-associated genes, several authors recently presented evidence indicating the presence of lectin-like NKC receptors and ligands in the proto-MHC region, trailing it back to protochordates (cite several).
Genes
NKC genes appear to be silenced or translocated in unique ways in various taxa, as is apparent by the presence of NKp30 genes in different chromosomes that contain MHC paralogous regions in fish, amphibians, reptiles and mammals (cite for each). The vast majority of NKC receptors, however, expanded in a species-dependent manner based upon selective pressures by successful immune-evasive pathogens (Lanier 2009). Therefore, it is important to note that MHC-I molecules play a major role in the continuous diversification of NKC receptors. Thus, the original genomic location of the receptors and ligands associated with immune function prior to genomic duplication facilitated, at least in part, the ability to co-evolve into a functional system. In contrast to MHC-I, MHC-II genes are limited to chromosome six and are functionally conserved in tetrapods, eluding to a delayed evolution of the MHC-II pathways.
Orthologous MHC-II and associated genes (DM and DO) are recognized in mammals, chickens and frogs (cite for each). The evolution of the MHC-II system of antigen processing can be predicted to arise based upon adaptation of pathogenic intracellular mechanisms to escape host phagocytosis within endosomal compartments (Casadevall, 2008). Interestingly, the recent genome sequencing of the atlantic cod revealed the loss of MHC-II genes and the compensatory expansion of MHC-I genes. Similar results have been found in various teleost fish species, suggesting that the absence of deep-water pathogens with endosomal escape mechanism led to the elimination of the MHC-II system in a significant proportion of vertebrates (Jakobsen et al. 2011, Dijkstra 2013). Thus, if the MHC-II system would not have developed in humans, we would heavily rely on expansion of the MHC-I genes and innate pattern recognition molecules. The flexibility and adaptability of the immune system genes is especially apparent in xenograft experiments performed on invertebrate species. Dishaw and Litman (2009) reported the ability of Hydractinia to reject a non-self graft by utilizing innate “histocompatibility loci”, alr1 and alr2.
Moreover, sea urchins have expanded the toll-like receptor and scavenger receptor genes by ~100 folds, suggesting an expandable gain of function to discern between self and non-self in the innate immune system (cite). The convergent evolution of various mechanisms to improve immune function in different taxa, demonstrates the selective role of environmental pressures on the genetic components of the immune system. The evolution of the MHC systems is linked to the emergence of their respective antigen-specific receptors, the TCRs (Rossjohn 2015). The genetic composition and functional structure of TCRs has been extensively studied (cite several). Genome-wide studies in multiple species indicate that all jawed vertebrates share the function of genetic recombination for unique antigen receptors, as well as the heterodimeric structures of the TCR membrane bound proteins (Rossjohn 2015).
The gain of gene recombination function in a common jawed ancestor is attributed to the horizontal transfer of a transposon that supplied the heptamer-nonamer repeats (RSS sequences) and the recombination activating genes (RAG1 and RAG2) (Koonin and Krupovic 2014). Recently, Huang et al. (2016) identified ProtoRAG in lancelets as the ancient DNA transposable element that allowed for the development of what we know today as our adaptive immune system. ProtoRAG exhibited terminal inverted repeats closely related to VDJ RSSs, tail-to-tail oriented introns with RAG1- and RAG2-like genes, as well as the ability to rejoin their inverted repeats using similar endonuclease activities (Huan 2016).
RAG1 and RAG2 genes are necessary for the function of the adaptive immune system, however it is debated whether the gain of these genes was sufficient to trigger the evolution of VDJ-mediated immunity. Fugmann et al. (2006) reported that the invertebrate Strongylocentrotus purpuratus (purple sea urchin) possessed homologous RAG1- and RAG2-like genes without apparent VDJ recombination. This evidence suggests that the horizontal transfer may have occurred in a common ancestor, with the evolution of VDJ recombination function in jawed vertebrates. A careful review by Muller et al. (2018) propose a compelling hypothesis with the generation of T-regulatory (Tregs) cells following the Cambrian explosion as the evolutionary bottleneck for the surge of the adaptive immune system in vertebrates. The authors argue that dominant (aka peripheral) tolerance had to be in place to control self-reactive clones, in order for the imperfect nature of negative selection to be metabolically advantageous for host survival (Muller 2018). In the absence of peripheral tolerance, one self-reacting clone could clonally expand leading to host death by self-inflicting mechanisms.
Tregs depend on Foxp3 as the master transcription factor, as it affects the expression of thousands of genes related to their function (Janeway). The timeline proposed by Muller and colleagues is supported by phylogenetic evidence of Foxp paralogues and other essential genes involved dominant tolerance found only in vertebrates, suggesting it occurred as a result of the gene duplication event (Santos et al. 2011, Smith & Keinath 2015). Thus, the “Big Bang” created the opportunity, by genetic duplication and chromosome accessibility, for the generation of a highly complex regulatory circuitry for the appropriate development of the adaptive immune system and the evolutionary success of vertebral species.
