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We have previously reported atypical SCID phenotype caused by hypomorphic <jats:italic>IL2RG<\/jats:italic> (NM_000206.3) c.172C\u2009&gt;\u2009T;p.(Pro58Ser) variant. Here, we have further investigated the index patient\u2019s abnormally large \u03b3\u03b4 T cell population in terms of function and phenotype by studying IL2RG cell surface expression, STAT tyrosine phosphorylation and blast formation in response to interleukin stimulation, immunophenotyping, TCRv\u03b3 sequencing, and target cell killing. In contrast to his \u237a\u03b2 T cells, the patient\u2019s \u03b3\u03b4 T cells showed normal IL2RG cell surface expression and normal or enhanced IL2RG-mediated signaling. V\u03b42\u2009+\u2009population was proportionally increased with a preponderance of memory phenotypes and high overall tendency towards perforin expression. The patient\u2019s \u03b3\u03b4 T cells showed enhanced cytotoxicity towards A549 cancer cells. His TCRv\u03b3 repertoire was versatile but sequencing of <jats:italic>IL2RG<\/jats:italic> revealed a novel c.534C\u2009&gt;\u2009A; p.(Phe178Leu) somatic missense variant restricted to \u03b3\u03b4 T cells. Over time this variant became predominant in \u03b3\u03b4 T cells, though initially present only in part of them. IL2RG-Pro58Ser\/Phe178Leu variant showed higher cell surface expression compared to IL2RG-Pro58Ser variant in stable HEK293 cell lines, suggesting that somatic p.(Phe178Leu) variant may at least partially rescue the pathogenic effect of germline p.(Pro58Ser) variant. In conclusion, our report indicates that expansion of \u03b3\u03b4 T cells associated with atypical SCID needs further studying and cannot exclusively be deemed as a homeostatic response to low numbers of conventional T cells.<\/jats:p>","DOI":"10.1007\/s10875-022-01375-6","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T12:03:56Z","timestamp":1666181036000},"page":"358-370","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Characterization of Expanded Gamma Delta T Cells from Atypical X-SCID Patient Reveals Preserved Function and IL2RG-Mediated Signaling"],"prefix":"10.1007","volume":"43","author":[{"given":"Elina A.","family":"Tuovinen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sakari","family":"P\u00f6ysti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Firas","family":"Hamdan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kim My","family":"Le","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salla","family":"Keskitalo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanja","family":"Turunen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L\u00e9a","family":"Minier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nanni","family":"Mamia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaarina","family":"Heiskanen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markku","family":"Varjosalo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo","family":"Cerullo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juha","family":"Kere","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikko R. 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