Effect of CD3δ Deficiency on Maturation of α/β and γ/δ T-Cell Lineages in Severe Combined Immunodeficiency

Abstract

he t-cell-receptor complex consists of the a and b or g and d variant chains, paired as mutually exclusive heterodimers in association with the invariant chains CD3 g , d , e , and z. T cells with a and b chains are referred to as a / b T cells, and those with g and d chains are called g / d T cells. During development , the CD3 protein complex plays an important part in the transition of thymocytes from CD4¡CD8¡ double-negative immature precursors to a CD4+CD8+ double-positive stage and finally to the mature CD4+CD8¡ or CD4¡CD8+ single-positive T cell. 1-5 Selective deficiency of CD3 component g , d , e , or z in mice, achieved by gene knockout, causes mild-to-severe, although incomplete, blockage of T-cell development. 6-10 Similarly , CD3 g or CD3 e deficiency in humans brings about a partial arrest of T-cell mat-uration and only moderate immunodeficiency. 11,12 We report a novel defect in the CD3 d gene in three members of a kindred with a form of severe combined immunodeficiency (SCID) characterized by the absence of T cells but normal numbers of B cells (T¡B+ SCID). These three patients had an early arrest in T-cell development, with a nearly complete absence of circulating mature T cells and a complete lack of g / d T cells. Our results suggest that, unlike CD3 e and CD3 g , CD3 d is essential for T-cell development. We studied a kindred of Mennonite descent that shared multiple consanguineous links across several generations. Three patients with SCID were identified in this family. SCID was diagnosed in Patient 1 immediately after birth, after an examination performed because of previous cases in the family (Patients 2 and 3). She subsequently underwent bone marrow transplantation and is alive and well, with full immune reconstitution, three years later. Patient 2, a male cousin of Patient 1, was admitted at the age of two months because of fever, tachypnea, and tachycardia. Rapidly developing respiratory arrest required assisted ventilation, and he died of multiorgan failure. Adenovirus was identified in stool, urine, and bronchial secretions. Patient 3, a male cousin of Patients 1 and 2, was well and thriving until two and a half months of age, when chronic diarrhea developed. At three and a half months of age, the patient was admitted with respiratory distress, lethargy, and jaundice. On examination , he was noted to have hepatomegaly, and liver-function tests were markedly abnormal. He was transferred from another hospital with increased respiratory distress and died 12 hours later from rapidly developing refractory hypotension, liver failure, pulmonary hemorrhage, disseminated intravascular coagulopathy, and hemorrhagic shock. Cytomegalovirus was identified in multiple tissues obtained at autopsy. Flow-cytometric analyses of peripheral-blood lymphocytes from these patients showed a slight reduction in total lymphocyte counts in Patients 1 and 2 and a marked t case report The New England Journal of Medicine Downloaded from nejm.org on August 2, 2024. For personal use only. No other uses without permission.