Genesis of Progressive T‐Cell Deficiency Owing to a Single Missense Mutation in the Common Gamma Chain Gene

• Published in: Scandinavian journal of immunology Vol. 54; no. 6; pp. 582 - 591
• Main Authors: Goldman, A. S., Palkowetz, K. H., Rudloff, H. E., Dallas, D. V., Schmalstieg, F. C.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.12.2001; Wiley Subscription Services, Inc
• Subjects: Adolescent; Adult; Annexin A5 - metabolism; Apoptosis; Base Sequence; Case-Control Studies; Child; DNA - genetics; Female; Genetic Linkage; Humans; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - immunology; Immunologic Deficiency Syndromes - metabolism; Immunologic Deficiency Syndromes - pathology; In Vitro Techniques; Interleukin Receptor Common gamma Subunit; Lymphocyte Activation; Lymphocyte Count; Male; Mutation, Missense; Necrosis; Pedigree; Propidium - metabolism; propidium iodide; Receptors, Interleukin-7 - genetics; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - ultrastructure; Telomere - ultrastructure; X Chromosome - genetics
• ISSN: 0300-9475; 1365-3083
• DOI: 10.1046/j.1365-3083.2001.01006.x

Patients with a moderate X‐linked combined immunodeficiency (XCID) owing to a single missense mutation in the common gamma chain (γc) gene (L→Q271) were found to have a progressive T‐cell deficiency. Blood T cells from four older subjects with XCIDL→Q271 were studied to ascertain the basis of that progression. Few CD4+ T cells displayed the phenotype (CD45RA+ CD62L+) or deletion circles from T‐cell receptor (TCR) Vβ‐gene rearrangements found in recent thymic emigrants. These deficiencies were more severe in older males with XCIDL→Q271. Relative frequencies of fresh CD4+ and CD8+ T cells that bound annexin V, an early indicator of programmed cell death, or propidium iodide, an indicator of cell necrosis, were greater in XCIDL→Q271 T cells than in normal fresh T cells. The binding of annexin V and propidium iodide to XCIDL→Q271 T cells increased marginally after stimulation with anti‐CD3, but binding by fresh or stimulated XCIDL→Q271 T cells exceeded that found in normal stimulated T cells. Also, telomeres from XCIDL→Q271 CD4+ T cells were shortened in these patients compared to normal young adults. It therefore appears that the thymus is dysfunctional and that mature T cells are not effectively rescued from apoptosis or replication senescence via γc‐mediated pathways in XCIDL→Q271.