The Camel Adaptive Immune Receptors Repertoire as a Singular Example of Structural and Functional Genomics

Abstract

The adaptive immune receptors repertoire is highly plastic, with its ability to produce antigen-binding molecules and select those with high affinity for their antigen. Species have developed diverse genetic and structural strategies to create their respective repertoires required for their survival in the different environments. Camelids, until now, considered as a case of evolutionary innovation because of their only heavy-chain antibodies, represent a new mammalian model particularly useful for understanding the role of diversity in the immune system function. Here, we review the structural and functional characteristics and the current status of the genomic organization of camel immunoglobulins (IG) or antibodies, α/ß and γ/δ T cell receptors (TR), and major histocompatibility complex (MHC). In camelid humoral response, in addition to the conventional antibodies, there are IG with “only-heavy-chain” (no light chain, and two identical heavy gamma chains lacking CH1 and with a VH domain designated as VHH). The unique features of these VHH offer advantages in biotechnology and for clinical applications. The TRG and TRD rearranged variable domains of Camelus dromedarius (Arabian camel) display somatic hypermutation (SHM), increasing the intrinsic structural stability in the γ/δ heterodimer and influencing the affinity maturation to a given antigen similar to immunoglobulin genes. The SHM increases the dromedary γ/δ repertoire diversity. In Camelus genus, the general structural organization of the TRB locus is similar to that of the other artiodactyl species, with a pool of TRBV genes positioned at the 5’ end of three in tandem D-J-C clusters, followed by a single TRBV gene with an inverted transcriptional orientation located at the 3’ end. At the difference of TRG and TRD, the diversity of the TRB variable domains is not shaped by SHM and depends from the classical combinatorial and junctional diversity. The MHC locus is located on chromosome 20 in Camelus dromedarius. Cytogenetic and comparative whole genome analyses revealed the order of the three major regions “Centromere-ClassII-ClassIII-ClassI”. Unexpectedly low extent of polymorphisms and haplotypes was observed in all Old World camels despite different geographic origins.

Evolution of the T-Cell Receptor (TR) Loci in the Adaptive Immune Response: The Tale of the TRG Locus in Mammals

“…However, cDNA sequencing clearly revealed that besides the combinatorial diversity and the introduction of N region diversity typical of all known IG and TR genes, a further mechanism enhances the TRG diversity in Camelus dromedarius . In line with previous reports [ 97 ], more recent studies [ 35 , 98 ] have provided direct evidence that somatic hypermutation (SHM) heavily contributes to the expansion of the γδ TR repertoire even in the absence of functional reiterated genome duplications. The frequency of mutations observed in the V-γ domain was comparable with that found in targeted genes in AID-induced T lymphomas [ 99 ], rearranged shark TRGV [ 71 ], and dromedary TRDV regions [ 100 ].…”

“…In most mammalian species, including human [ 20 , 21 ], mouse [ 22 ], chimpanzee and rhesus monkey [ 23 ], dog [ 24 ], rabbit [ 25 ], ferret [ 26 ], and cat [ 27 ], two TRBD-J-C clusters exist. In contrast, in the cetartiodactyl lineage [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ], a duplication event within the 3′ end of the TRB locus led to the generation of a third TRBD-J-C cluster, increasing the number of TRBD and TRBJ genes available for the somatic rearrangements.…”

“…This observation (or consideration) comes from analysis of the TRB and TRA/TRD loci, which retain a conserved general gene arrangement and, although these regions appear to have been evolving dynamically in each eutherian mammalian species, a gross order of genes is still maintained. As a matter of fact, phylogenetic analysis conducted on the TRBV and TRAV genes showed that the V genes from different mammals intermingle rather than forming separate clades, proving that duplications of ancestral genes followed by diversification is the major mode of evolution [ 26 , 27 , 35 , 37 , 40 ]. This rule also fits also the TRG genes, despite the structure of the TRG locus differing considerably across species.…”

The expansion of the TRB and TRG genes in domestic goats (Capra hircus) is characteristic of the ruminant species

“…If ancient gene duplications within the TRB locus led to the generation of the different TRBV subgroups shared among mammals [ 48 ], in ruminants the framework of the TRBV germline repertoire evolved with a more recent expansion of two main TRBV subgroups rather than with the emergence of diverse TRBV subgroups. Overall, this extensive gene expansion resulted in ruminant species (goat, sheep and cattle) possessing a germline TRBV repertoire with the highest number of genes among all the mammalian species studied so far [ 7 , 11 ], including other artiodactyl species such as pigs and camels [ 14 – 17 ].…”

The Expansion of the TRB and TRG Genes in Domestic Goats (Capra hircus) is Characteristic of the Ruminant Species

“…If ancient gene duplications within the TRB locus led to the generation of the different TRBV subgroups shared among mammals [45], in ruminants the framework of the TRBV germline repertoire evolved with a more recent expansion of two main TRBV subgroups rather than with the emergence of diverse TRBV subgroups. Overall, this extensive gene expansion resulted in ruminant species (goat, sheep and cattle) possessing a germline TRBV repertoire with the highest number of genes among all the mammalian species studied so far [7,11], including other artiodactyl species such as pigs and camels [14][15][16][17].…”