学位論文内容の要旨（Summary of dissertation）

博士の専攻分野の名称

博士（医 学）（Degree conferred: Doctor of Philosophy）

氏 名 ラニア ハッサン モハメド ハッサン
（Name of recipient: Rania Hassan Mohamed Hassan）

学位論文題名（Title of dissertation）
The SKINT1-like Gene Is Inactivated in Hominoids But Not in All Primate Species: Implications for theOrigin of Dendritic Epidermal T Cells（ヒト及び類人猿で不活化している SKINT1 様遺伝子の旧世界ザルでの機能残存と樹状表皮 T 細胞の由来に関する検討）

Background:The γδ+ dendritic epidermal T-cells (DETCs) are the residential T-cells in mouse epidermis
expressing the invariant Vγ5Vδ1 TCR and have a critical role for skin immunosurveillance andhomeostasis. DETCs are generated by positive selection in the fetal thymus during the narrow period
from embryonic day 14.5 to 18.5, after which they migrate to the skin. Skint1 gene is composed of 7
coding exons expressing an immunoglobulin protein exclusively in thymic epithelial cells andkeratinocytes at embryonic day 15 and continue to adulthood. Skint1 duplicated in mice to form Skint
family which is in turn considered as a member of butyrophilin (BTN) family. Skint-1 protein issuggested as the first and indispensible component for selection of the invariant DETC. Rat and cow
have Skint1 orthologs with protein topology and structure similar to that of mouse, in addition, they havehigh population of DETC-like cells expressing γδ TCR with limited variability. In contrast, Skint1 has
multiple in-frame premature termination codons in both human and chimpanzee, moreover, humans
don't posses neither high population nor monomorphic epidermal γδ T cells. It is noteworthy that thepresence of Skint1 is correlated with presence of a restricted cutaneous T cell population. It will be ofparticular interest to determine when Skint1 rendered inactive in the mammalian phylogeny andconcomitantly DETCs are lost.
Methods: To detect at which stage in primate evolution Skint1 inactivation took place, we analyzed thepredicted SKINT1L sequences in primate species. We called here Skint1 of all mammalian species otherthan mice as SKINT1L. Cloning and sequencing were done to characterize the SKINT1L of cynomolgus

macaque as a representative of Old World Monkeys (OWM). Using RT-PCR and immunohistochemical
staining, we also examined the epidermal γδ T cell population in cynomolgus macaque investigating thefunctionality of SKINT1L. To better understand the evolution of the Skint1/SKINT1L gene family, andmore generally the entire SKINT gene family, we extended our bioinformatics to mammals other thanprimates.
Results: We found that all hominoids SKINT1L has a common inactivating mutation, but that Old Worldmonkeys have apparently functional SKINT1L sequences and the epidermal resident γδ T cells incynomolgus macaques contains a population of dendritic-shaped γδ T cells expressing an invariant
Vγ10Vδ1 T-cell receptors. We demonstrated also that SKINT1L emerged in an ancestor of placental
mammals, but was inactivated or lost multiple times in mammalian evolution.
Discussion and conclusions: SKINTL family and in turn SKINT1L are highly evolved through themammalian evolution, They have been emerged in an ancestor of eutheria and lost or inactivatedmultiple times in the mammalian phylogeny which suggest a concomitant loss of the skin-resident γδ Tcells in the orders lacking in consequence to SKINT1L deficiency.