Case report: Artificial thymic organoids facilitate clinical decisions for a patient with a TP63 variant and severe persistent T cell lymphopenia

• Published in: Frontiers in immunology 2024-09, Vol.15, p.1438383
• Main Authors: Gall, Alevtina, Bosticardo, Marita, Ma, Stacey, Chen, Karin, Amini, Kayla, Pala, Francesca, Delmonte, Ottavia M, Wenger, Tara, Bamshad, Michael, Sleasman, John, Blessing, Matthew, van Oers, Nicolai S C, Notarangelo, Luigi D, de la Morena, M Teresa
• Format: Article
• Language: English
• Subjects: ankyloblepharon-ectodermal defects-cleft lip/palate (AEC); artificial thymic organoids; Cell Differentiation; cultured thymus tissue implantation (CTTI); ectrodactyly-ectodermal dysplasia clefting (EEC); Female; Humans; Immunology; Infant, Newborn; Lymphopenia - genetics; Lymphopenia - immunology; Mutation; Organoids; T cell lymphopenia; T-Lymphocytes - immunology; Thymus Gland - immunology; TP63; Transcription Factors - genetics; Tumor Suppressor Proteins - genetics
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2024.1438383

Pathogenic variants in the transcription factor are associated with clinically overlapping syndromes including ectrodactyly-ectodermal dysplasia clefting (EEC) and ankyloblepharon-ectodermal defects-cleft lip/palate (AEC). T cell lymphopenia has rarely been described in individuals with variants and the cause of the T cell defect is unclear. Here, we present a case of a female infant born with -related syndrome and profound T cell lymphopenia, first uncovered through newborn screening. Flow cytometry analysis revealed low CD4+ naïve T cells and nearly absent CD8+ T cells with intact B and NK cell compartments. A heterozygous pathogenic variant c.1040 G>A (C347Y) in exon 8 of was identified. An artificial thymic organoid system, to assess the intrinsic ability of the patient's hematopoietic cells to develop into T cells, was performed twice using separate peripheral blood samples. T cell differentiation was evident with the artificial organoid system, suggesting that a thymic stromal cell defect may be the cause of the T cell lymphopenia. Consistent with this, interrogation of publicly available data indicated that expression in the human thymus is restricted to thymic epithelial cells. Based on these data, congenital athymia was suspected and the patient received an allogenic cultured thymus tissue implant (CTTI). This is the first report of suspected congenital athymia and attempted treatment with CTTI associated with variant. At 9 months post-implant, peripheral lymphocyte analysis revealed measurable T cell receptor excision circles and presence of CD4+ recent thymic emigrants suggestive of early thymopoiesis. She will continue regular monitoring to ensure restoration of T cell immunity.