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.