Modification of cellular and humoral immunity by somatically reverted T cells in X-linked lymphoproliferative syndrome type 1

Hoshino, Akihiro; Yang, Xi; Tanita, Kay; Yoshida, Kenichi; Ono, Tomotada; Nishida, Naonori; Kanzaki, Takeyuki; Goi, Kumiko; Fujino, Hisanori; Ohshima, Koichi; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Ogawa, Seishi; Kojima, Seiji; Morio, Tomohiro; Kanegane, Hirokazu

doi:10.1016/j.jaci.2018.07.044

Cited by 10 publications

(22 citation statements)

References 17 publications

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“…We completed our validation in June of 2014, and since then, we have observed this identical CD8 T cell-restricted bimodal SAP expression pattern in only one additional patient, a 15-y-old male with a confirmed hypomorphic mutation in the gene encoding the X-linked inhibitor of apoptosis protein (which causes X-linked lymphoproliferative disease type 2) and a positive history of EBV infection early in childhood (unfortunately, we were not able to consent this individual for this study). Interestingly, this same 1C9 Ab clone-associated CD8 T cell-restricted bimodal expression pattern was also observed in three subjects evaluated in a recent study examining humoral and cellular immune responses in XLPD-Type 1 patients displaying spontaneous somatic reversion of their SAP mutations, which can occur in the face of selective pressure mediated by EBV exposure (14,16). And this bimodal pattern is clearly distinct from what is observed in XLPD-Type 1 female carriers that harbor SAP + and SAP 2 lymphocyte subsets (7).…”

Section: Introductionsupporting

confidence: 61%

“…Furthermore, this clone 1C9-associated CD8 T cell-restricted bimodal pattern of SAP expression (hereafter referred to as 1C9-hi and 1C9-lo) is clearly distinct from the phenotype observed in XLPD-Type 1 female carriers (SAP + and SAP 2 ) in which the SAP 2 population overlaps with the isotype control Ab signal (7). Moreover, as mentioned in the introduction, this identical 1C9 Ab cloneassociated CD8 T cell-restricted bimodal pattern of SAP expression is also portrayed, but was not formally evaluated, in a recent publication examining immune responses in three XLPD-Type 1 patients displaying spontaneous reversion of their SAP mutations (16). We also examined SAP expression in donors 1 and 2 with the rat-derived XLP-1D12 SAP Ab clone, which unlike the 1C9 Ab clone, consistently displayed the conventional unimodal pattern of SAP expression ( Fig.…”

Section: Clone 1c9-associated Cd8 T Cell-restricted Bimodal Pattern Omentioning

confidence: 96%

“…Briefly, aliquots of whole blood samples collected in sodium EDTAtreated blood collection tubes were analyzed within 24 h of blood draw. They were first treated with Human TruStain FcX (BioLegend), https://doi.org/10.4049/immunohorizons.1900060 fixed, permeabilized, and then incubated with either the isotype control Ab (mouse IgG2a, k; clone MOPC-173) (BD Biosciences) or purified mouse anti-human SAP mAb (clone 1C9) (Abnova, Taipei, Taiwan) (5,7,(10)(11)(12)(13)(14)(15)(16). Both the isotype control Ab and 1C9 clone were used at the recommended dosage (1 mg/test).…”

Section: Detection Of Sap By Flow Cytometrymentioning

confidence: 99%

“…Analyses performed in SLE patients and controls have demonstrated that SAP expression levels are higher in effector/memory CD4 T cells compared with naive CD4 T cells, and a separate study demonstrated that memory T cells harbor a greater proportion of SAP + T cells compared with naive T cells (8,29). Additionally, an examination of cases of spontaneous somatic reversion of the SAP mutations in XLPD-Type 1 patients has shown that this reversion is restricted to the memory CD8 T cell and CD4 T cell subsets (14,16). Consistent with these previous reports, we observed that memory (CD45RO + ) CD8 T cells from donors 3 and 4 that display the conventional unimodal pattern of SAP expression with the 1C9-SAP Ab clone also expressed higher levels of SAP in terms of median fluorescence intensity (MFI) (2.5-4 times greater than the [CD45RO 2 ] CD8 T cells) (Supplemental Fig.…”

Section: C9-hi Cd8 T Cells Display a Predominantly Memory Phenotypementioning

confidence: 99%

“…We are a Clinical Laboratory Improvement Amendmentscertified and College of American Pathologists-accredited diagnostic immunology laboratory, and XLPD-Type 1 is one of several rare primary immunodeficiency disorders for which we offer a rapid flow cytometry-based, clinically validated diagnostic test. As part of this validation process, we screened 54 healthy donors to determine the normal range of SAP expression in defined lymphocyte subsets using the widely reported 1C9-SAP Ab clone (5,7,(10)(11)(12)(13)(14)(15)(16). During this effort, we encountered two healthy donors (one adult male and one adult female, both over 30 y of age, and the female donor has three healthy male and female offspring), in whom, specifically, the CD8 T cells consistently displayed a unique bimodal pattern of SAP expression observed with the 1C9-SAP Ab clone.…”

Section: Introductionmentioning

confidence: 99%

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Detailed Phenotypic and Functional Characterization of a Rare, Antibody-Dependent SLAM-Associated Protein Expression Pattern

et al. 2020

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SLAM-associated protein (SAP) is an adaptor molecule that facilitates critical effector functions in immune cells, and its deficiency causes X-linked lymphoproliferative disease type 1 in which effector responses directed against EBV are severely compromised. The primary objective of this study was to phenotypically and functionally characterize a rare, CD8 T cell-restricted bimodal SAP expression pattern observed in healthy, human donors with the widely used 1C9-SAP mAb clone. We initially observed this pattern during the clinical validation of our flow cytometry-based assay to diagnose X-linked lymphoproliferative disease type 1 in our laboratory. For this validation study, we used multiparameter flow cytometry to identify cytosolic SAP expression in lymphocyte subsets, and CD8 T cells from the donors displaying the rare SAP expression pattern mentioned above were separately further evaluated by intracellular cytokine and CD107a staining to examine polyfunctionality following PMA/ionomycin and HLA class I allele-restricted EBV peptide epitope-induced T cell activation. Our data revealed that SAP 1C9-hi CD8 T cells clearly displayed higher polyfunctional responses versus SAP 1C9-lo CD8 T cells following PMA/ionomycin stimulation. Furthermore, polyfunctional EBV-specific CD8 T cell responses segregated with the SAP 1C9-hi CD8 T cells and not the SAP 1C9-lo CD8 T cells. Additionally, and rather intriguingly, short-and long-term T cell stimulation selectively diminished the signal for the 1C9-hi subset. Overall, our data suggest that although rare, this unique SAP expression pattern merits further evaluation as it has the potential to provide some insight into fundamental processes as they might relate to host-pathogen dynamics. ImmunoHorizons, 2020, 4: 153-164.

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Section: Introductionsupporting

confidence: 61%

Section: Clone 1c9-associated Cd8 T Cell-restricted Bimodal Pattern Omentioning

confidence: 96%

Section: Detection Of Sap By Flow Cytometrymentioning

confidence: 99%

Section: C9-hi Cd8 T Cells Display a Predominantly Memory Phenotypementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Detailed Phenotypic and Functional Characterization of a Rare, Antibody-Dependent SLAM-Associated Protein Expression Pattern

et al. 2020

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Genetic Mosaicism as a Cause of Inborn Errors of Immunity

Aluri

Cooper

2021

J Clin Immunol

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Inborn errors of immunity (IEIs) are a heterogeneous group of disorders due to genetic defects in the immune response that have a broad clinical spectrum. Diagnosis of the precise genetic cause of IEI has led to improved care and treatment of patients; however, genetic diagnosis using standard approaches is only successful in ~40% of patients and is particularly challenging in “sporadic” cases without a family history. Standard genetic testing for IEI evaluates for germline changes in genes encoding proteins important for the immune response. It is now clear that IEI can also arise from de novo mutations leading to genetic variants present in germ cells and/or somatic cells. In particular, somatic mosaicism, i.e., post-zygotic genetic changes in DNA sequence, is emerging as a significant contributor to IEI. Testing for somatic mosaicism can be challenging, and both older sequencing techniques such as Sanger sequencing and newer next-generation sequencing may not be sensitive enough to detect variants depending on the platform and analysis tools used. Investigation of multiple tissue samples and specifically targeting sequence technologies to detect low frequency variants is important for detection of variants. This review examines the role and functional consequences of genetic mosaicism in IEI. We emphasize the need to refine the current exome and genome analysis pipeline to efficiently identify mosaic variants and recommend considering somatic mosaicism in disease discovery and in the first-tier of genetic analysis.

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