Comparison of Reptilian Genomes Reveals Deletions Associated with the Natural Loss of γδ T Cells in Squamates

Abstract

T lymphocytes or T cells are key components of the vertebrate response to pathogens and cancer. There are two T cell classes based on their TCRs, αβ T cells and γδ T cells, and each plays a critical role in immune responses. The squamate reptiles may be unique among the vertebrate lineages by lacking an entire class of T cells, the γδ T cells. In this study, we investigated the basis of the loss of the γδ T cells in squamates. The genome and transcriptome of a sleepy lizard, the skink Tiliqua rugosa, were compared with those of tuatara, Sphenodon punctatus, the last living member of the Rhynchocephalian reptiles. We demonstrate that the lack of TCRγ and TCRδ transcripts in the skink are due to large deletions in the T. rugosa genome. We also show that tuataras are on a growing list of species, including sharks, frogs, birds, alligators, and platypus, that can use an atypical TCRδ that appears to be a chimera of a TCR chain with an Ab-like Ag-binding domain. Tuatara represents the nearest living relative to squamates that retain γδ T cells. The loss of γδTCR in the skink is due to genomic deletions that appear to be conserved in other squamates. The genes encoding the αβTCR chains in the skink do not appear to have increased in complexity to compensate for the loss of γδ T cells.

Identification of distinct functional thymic programming of fetal and pediatric human γδ thymocytes via single-cell analysis

“…γδ T cells are the 'third' type of lymphocytes, besides αβ T cells and B cells, that can rearrange gene segments at the DNA level in order to generate variable antigen receptors 1,2 . These three cell lineages have been conserved seemingly since the emergence of jawed vertebrates, with the notable exception of squamate reptiles 3 , while a similar tripartite subdivision exists even in jawless vertebrates such as lamprey and hagfish 4,5 . Emerging evidence suggests that their role in early life immunity might be a critical factor for this striking evolutionary conservation 2,[6][7][8][9][10][11][12][13][14][15] .…”

Structure and evolution of the squamate major histocompatibility complex as revealed by two Anolis lizard genomes

“…Significant progress has even been made characterizing the MHC and immune biology in much smaller amniote clades like crocodilians, turtles, and tuatara. This research bias restricts our knowledge of the squamate MHC and immunity, though some early studies indicate that squamates may have unique immunological characteristics, such as a lack of γδ T cells ( Morrissey et al, 2022 ). Scientists’ ability to understand and respond to squamate-specific pathogens, such as the emerging snake fungal disease ( Lorch et al, 2016 ; Franklinos et al, 2017 ), may also be hindered by limited knowledge of squamate MHC and immunity.…”

Surfing on the waves of the human γδ T cell ontogenic sea

“…T cells besides αβ T cells, which is likely related to the fundamental different antigen recognition mechanisms between these two T cell lineages. 2,6,7 The absence of the γδ T cell lineage in squamates 8 and of the CD4+ αβ T cell subset in Atlantic cod 9 indicates that in certain species, selection processes may have favored overlapping functions in different lymphocyte lineages. γδ T cells can play various roles in the immune system including protection against cancer and infection, and they are increasingly being studied as a cellular target in cancer immunotherapy, where their MHC-independent activation provides a main advantage over αβ T cell-based approaches.…”

“…A more extreme exception is represented by the squamata lineage (squamates), as this family of reptiles has been reported to have lost the TCR γ and δ loci during evolution. 8 When αβ T cells appear in squamate ontogeny is not known. The ontogeny of the T cell compartment in swine (Sus scrofa domesticus) and sheep (Ovis aries) displays similarities with humans, with adult-like levels of γδ thymocytes and a diverse TCR repertoire before birth.…”