Genesis of progressive T-cell deficiency owing to a single missense mutation in the common gamma chain gene.
Patients with a moderate X-linked combined immunodeficiency (XCID) owing to a single missense mutation in the common gamma chain (gammac) 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) Vbeta-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 gamma-mediated pathways in XCIDL-->Q271.
Goldman
A S
AS
The Division of Immunology, Allergy, and Rheumatology, The University of Texas Medical Branch, Galveston 77555-0369, USA.
Palkowetz
K H
KH
Rudloff
H E
HE
Dallas
D V
DV
Schmalstieg
F C
FC
D000293:Adolescent; D000328:Adult; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D001483:Base Sequence; D016022:Case-Control Studies; D002648:Child; D004247:DNA / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D053631:Interleukin Receptor Common gamma Subunit; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008297:Male; D020125:Mutation, Missense; D009336:Necrosis; D010375:Pedigree; D011419:Propidium / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D016615:Telomere / Q000648:ultrastructure; D014960:X Chromosome / Q000235:genetics
D017304:Annexin A5; C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit; D020395:Receptors, Interleukin-7; D011419:Propidium; D004247:DNA