The SKINT1-Like Gene Is Inactivated in Hominoids But Not in All Primate Species: Implications for the Origin of Dendritic Epidermal T Cells

Abstract

Dendritic epidermal T cells, which express an invariant Vγ5Vδ1 T-cell receptor and account for 95% of all resident T cells in the mouse epidermis, play a critical role in skin immune surveillance. These γδ T cells are generated by positive selection in the fetal thymus, after which they migrate to the skin. The development of dendritic epidermal T cells is critically dependent on the Skint1 gene expressed specifically in keratinocytes and thymic epithelial cells, suggesting an indispensable role for Skint1 in the selection machinery for specific intraepithelial lymphocytes. Phylogenetically, rodents have functional SKINT1 molecules, but humans and chimpanzees have a SKINT1-like (SKINT1L) gene with multiple inactivating mutations. In the present study, we analyzed SKINT1L sequences in representative primate species and found that all hominoid species have a common inactivating mutation, but that Old World monkeys such as olive baboons, green monkeys, cynomolgus macaques and rhesus macaques have apparently functional SKINT1L sequences, indicating that SKINT1L was inactivated in a common ancestor of hominoids. Interestingly, the epidermis of cynomolgus macaques contained a population of dendritic-shaped γδ T cells expressing a semi-invariant Vγ10/Vδ1 T-cell receptor. However, this population of macaque T cells differed from rodent dendritic epidermal T cells in that their Vγ10/Vδ1 T-cell receptors displayed junctional diversity and expression of Vγ10 was not epidermis-specific. Therefore, macaques do not appear to have rodent-type dendritic epidermal T cells despite having apparently functional SKINT1L. Comprehensive bioinformatics analysis indicates that SKINT1L emerged in an ancestor of placental mammals but was inactivated or lost multiple times in mammalian evolution and that Skint1 arose by gene duplication in a rodent lineage, suggesting that authentic dendritic epidermal T cells are presumably unique to rodents.

Characterization of a Putative Receptor Binding Surface on Skint-1, a Critical Determinant of Dendritic Epidermal T Cell Selection

“…Skint-1 is the first identified putative selecting element for a major γδ T cell compartment in rodents. Moreover, although all hominoid species appear to have inactivating mutations in the Skint-1- like gene, recent analyses suggest Old World primates do have apparently functional Skint-1 genes, and may possess dendritic epidermal T cell populations ( 39 ). As such, it promises to be of general relevance to other intraepithelial compartments and/or other non-MHC restricted T cells ( 15 , 16 ), in which regard, its biology may inform that of its relative, BTN3A1, which is essential for human peripheral blood γδ T cell recognition of so-called P-Ags ( 36 ).…”

Impaired Epidermal to Dendritic T Cell Signaling Slows Wound Repair in Aged Skin

“…They harbor a null mutation in s election and up k eep of in traepithelial T -cells 1 ( Skint1 ), lack canonical Vγ5Vδ1 expressing DETCs. Skint1 , is the founding member of a family ( Skint1-11 ) of butyrophilin-like proteins with containing transmembrane spanning domains and extracellular IgV, and IgC domains (Mohamed et al, 2015). During development, Skint1 is expressed by thymic epithelial cells, promoting functional differentiation of DETC progenitors (Boyden et al, 2008).…”

Functional Phenotypes of Human Vγ9Vδ2 T Cells in Lymphoid Stress Surveillance

“…The concept of btnl family member-mediated selection of γδ T cells with specific T cell receptor (TCR) heterodimers to tissues has since been extended to mouse Vγ7 γδ T cells localising to the intestine and forming the majority of intraepithelial lymphocytes by interacting with heterodimers of btnl1 and 6 [9]. Whilst humans do not have DETC, most likely due to mutations in the SKINT gene locus [10], conservation of this mechanism was shown through human Vγ4 γδ T cells, which localise to human gut epithelium, where preferentially expressed BTNL3/8 heterodimers induce γδ TCR down-regulation [9]. It has since been confirmed that BTNL3 directly binds to human Vγ4 TCRs via the germ line encoded complementarity determining region (CDR)2, which allows the γδ TCR to additionally bind to antigens via the somatically recombined CDR3 separating tissue selection from antigen recognition [11,12].…”