Dataset Information

Impact of maternal engrafted cytomegalovirus-specific CD8⁺ T cells in a patient with severe combined immunodeficiency.

ABSTRACT:

Objectives

In patients with severe combined immunodeficiency (SCID), the immune system often fails to eradicate maternal cells that enter the foetus via the placenta, resulting in transplacental maternal engraftment (TME) syndrome. However, the clinical significance of TME has not been comprehensively elucidated.

Methods

Here, we describe a patient with SCID with a novel frameshift IL2RG mutation associated with maternal engrafted CD8⁺ T cells that had been expanded by viral infection. To evaluate the origin of the expanded T cells, we HLA-typed the myeloid and T cells of the patient and analysed the immunological characteristics of the expanded CD8⁺ T cells using T-cell receptor (TCR) repertoire and flow cytometry analysis.

Results

In our patient, the maternal engrafted CD8⁺ T cells expanded and exerted in vitro antiviral function against human cytomegalovirus (CMV) infection before and after haematopoietic cell transplantation (HCT). After haploidentical HCT from the maternal donor, maternal engrafted CMV-specific CD8⁺ T cells were maintained, successfully proliferated and activated against CMV. We found no evidence of acute graft-versus-host disease or infectious complications other than recurrent episodes of CMV viraemia, which were well controlled by ganciclovir and, possibly by, the maternal engrafted CMV-specific CD8⁺ T cells.

Conclusion

Our findings elucidate a possible functional role of TME in controlling CMV infection in patient with SCID and suggest an optimal strategy for donor selection in patients with SCID with TME.

SUBMITTER: Koh JY

PROVIDER: S-EPMC8043123 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Severe combined immunodeficiency (SCID) is described as the lack of functional T and B cells. In some cases, mutant genes encoding proteins involved in the process of VDJ recombination retain partial activity and are classified as hypomorphs. Hypomorphic activity in the products from these genes can function in the development of T and B cells and is referred to as a leaky phenotype in patients and animals diagnosed with SCID. We previously described two natural, single nucleotide variants in ARTEMIS (DCLR1EC) in a line of Yorkshire pigs that resulted in SCID. One allele contains a splice site mutation within intron 8 of the ARTEMIS gene (ART16), while the other mutation is within exon 10 that results in a premature stop codon (ART12). While initially characterized as SCID and lacking normal levels of circulating lymphoid cells, low levels of CD3ε+ cells can be detected in most SCID animals. Upon further assessment, we found that ART16/16, and ART12/12 SCID pigs had abnormally small populations of CD3ε+ cells, but not CD79α+ cells, in circulation and lymph nodes. Newborn pigs (0 days of age) had CD3ε+ cells within lymph nodes prior to any environmental exposure. CD3ε+ cells in SCID pigs appeared to have a skewed CD4α+CD8α+CD8β- T helper memory phenotype. Additionally, in some pigs, rearranged VDJ joints were detected in lymph node cells as probed by PCR amplification of TCRδ V5 and J1 genomic loci, as well as TCRβ V20 and J1.1, providing molecular evidence of residual Artemis activity. We additionally confirmed that TCRα and TCRδ constant region transcripts were expressed in the thymic and lymph node tissues of SCID pigs; although the expression pattern was abnormal compared to carrier animals. The leaky phenotype is important to characterize, as SCID pigs are an important tool for biomedical research and this additional phenotype may need to be considered. The pig model also provides a relevant model for hypomorphic human SCID patients.

Project description:Background: Severe combined immunodeficiency (SCID) is characterized by arrested T lymphocyte production and B lymphocyte dysfunction, resulting in life-threatening infections. Early diagnosis of SCID through population-based newborn screening (NBS) optimizes clinical management and outcomes, and also permits identification of previously unknown factors essential for human lymphocyte development. Methods: SCID was detected, prior to onset of infections, by NBS of T cell receptor excision circles, a biomarker for thymic output. Upon confirmation, the affected baby was treated by allogeneic hematopoietic cell transplantation (HCT). The genetic cause was sought by exome sequencing of the patient and parents, followed by functional analysis of a prioritized candidate gene using human hematopoietic stem cells (HSC) and zebrafish embryos. Results: An infant with leaky SCID, craniofacial and dermal abnormalities, and absent corpus callosum had his immune deficit fully corrected by HCT. Exome sequencing revealed a heterozygous, de novo, missense mutation pN441K in BCL11B. The mutant Bcl11b protein had dominant negative activity, abrogating the ability of wild type Bcl11b to bind DNA, arresting T cell lineage development and disrupting HSC migration, revealing a novel function of Bcl11b. The patientâs defects, recapitulated in Bcl11b-deficient zebrafish, were reversed by ectopic expression of intact, but not mutant, human BCL11B. Conclusions: Newborn screening facilitated treatment and identification of a novel etiology for human SCID. Coupling exome sequencing with candidate gene evaluation in human HSC and in zebrafish revealed that a constitutional BCL11B mutation causes human multisystem anomalies with SCID, while also revealing a novel, pre-thymic role for Bcl11b in hematopoietic progenitors. 3 samples were analyzed in duplicate, Sample 1 was human HSC transduced with GFP only lentivirus which served as controls, Sample 2 was human HSC transduced with lentivirus expressing FLAG-tagged WT BCL11B and GFP, Sample 3 was human HSC transduced with lentivirus expressing FLAG-tagged mutant BCL11B and GFP

Dataset Information

Impact of maternal engrafted cytomegalovirus-specific CD8⁺ T cells in a patient with severe combined immunodeficiency.

Objectives

Methods

Results

Conclusion

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Impact of maternal engrafted cytomegalovirus-specific CD8+ T cells in a patient with severe combined immunodeficiency.

Objectives

Methods

Results

Conclusion

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Impact of maternal engrafted cytomegalovirus-specific CD8⁺ T cells in a patient with severe combined immunodeficiency.