IntroductionOmenn syndrome (OS) is a combined immunodeficiency characterized by early-onset erythroderma, lymphadenopathy, hepatosplenomegaly, and severe infections. Patients with OS have a variable number of autologous, oligoclonal, and activated T cells that infiltrate and damage target tissues. 1,2 OS may be due to heterogeneous gene defects that impair, but do not abolish, thymic T-cell development. In particular, hypomorphic mutations of the RAG1 or RAG2 genes, involved in V(D)J recombination, are a common cause for OS. [3][4][5] The same defects may lead to a spectrum of clinical and immunologic phenotypes that also include typical T Ϫ B Ϫ severe combined immune deficiency (SCID) or leaky SCID with residual presence of activated T cells, in the absence of typical features of OS. 4,6 The clinical and pathological features of OS are suggestive of T-cell-mediated autoimmunity. In keeping with this hypothesis, we have found that expression of autoimmune regulator (AIRE) and of AIRE-dependent tissue-specific transcripts is reduced in the thymus from patients with OS, possibly contributing to impaired central tolerance. 7 In addition, defects of regulatory T cells have been also hypothesized in patients with OS. 8 Both abnormalities have been confirmed in a newly generated murine model of OS. 9 However, the possible contributory role of other immunomodulatory components in determining the phenotype of OS has not been carefully evaluated.Natural killer T (NKT) cells represent a population of cells with significant immunomodulatory properties. 10 In humans, most NKT cells recognize glycolipids presented in the context of CD1d molecules and express NK-cell markers along with an invariant T-cell receptor (TCR) with a V␣24-J␣18 rearrangement. NKT cells expressing the invariant TCR (iNKT) can be identified using ␣-galactosylceramide (␣-GalCer)-loaded CD1d tetramers. 11 iNKT cells are generated in the thymus from CD4 ϩ CD8 ϩ thymocytes that rearrange the invariant TCR and are directed to the NKT lineage following cognate interactions with CD1d-expressing cortical thymocytes. 12,13 Therefore, NKT cell development is absolutely dependent on V(D)J recombination, consistent with the observation that iNKT cells are severely reduced in a Rag2 knock-in mouse model of OS. 9 In this study, we provide the first evidence that iNKT cells are absent in peripheral blood of patients with hypomorphic RAG mutations, a situation where substantial numbers of autoreactive T cells develop. We speculate that the absence of iNKT cells may contribute to the pathophysiology of OS. Methods PatientsFive unrelated patients with hypomorphic RAG defects were studied; 4 of them (patients 1, 2, 3, and 5) had typical OS, whereas patient 4 had the phenotype of T ϩ B Ϫ leaky SCID (Table 1). Informed consent was obtained in accordance with the Declaration of Helsinki and according to protocols approved by Children's Hospital, Boston; the Department of Pediatrics, University, Brescia, Italy; and the Department of Pediatrics, Tor Vergata University, Rome, ...