Lack of iNKT cells in patients with combined immune deficiency due to hypomorphic RAG mutations

Abstract

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, ...

NKT cell development in the absence of the autoimmune regulator gene (Aire)

“…A similar correlation between Aire expression and NKT cell numbers was reported in lymphotoxin-deficient mice [23,24], although the link between the expression of lymphotoxin and Aire-dependent genes has been disputed in more recent studies [25][26][27]. Human patients (and a mouse model) of Omenn syndrome [28,29] also have reduced levels of Aire and NKT cells and it is interesting to note that the severe NKT cell deficit evident in NOD mice coincides with significant morphological abnormalities among Aire 1 medullary cells in the thymus [20].…”

Late-onset combined immune deficiency associated to skin granuloma due to heterozygous compound mutations in RAG1 gene in a 14years old male

“…Notarangelo's group has demonstrated a defect in iNKT cell generation in Omenn patients [17]. Flow cytometric quantification of peripheral blood NKT cells was organized when patient was 14 years 6 months NKT cells identified as CD3+, TCRVa24+ and TCRVb11+ co-expressing lymphocytes.…”

DOCK8 is critical for the survival and function of NKT cells

“…Several immunodeficiency syndromes have been associated with NKT cell deficiency such as WiskottAldrich syndrome, 36,37 Omenn's syndrome, 38 and X-linked lymphoproliferative (XLP) disease. 39 NKT cells play an important role in the immediate response to pathogens through mechanisms including the release of inflammatory cytokines and activation of innate immune cells such as NK cells.…”