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 (γ_c) gene (L→Q271) were found to have a progressive T-cell deficiency. Blood T cells from four older subjects with XCID^L→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 XCID^L→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 XCID^L→Q271 T cells than in normal fresh T cells. The binding of annexin V and propidium iodide to XCID^L→Q271 T cells increased marginally after stimulation with anti-CD3, but binding by fresh or stimulated XCID^L→Q271 T cells exceeded that found in normal stimulated T cells. Also, telomeres from XCID^L→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 γ_c-mediated pathways in XCID^L→Q271.