Development of autologous, oligoclonal, poorly functioning T lymphocytes in a patient with autosomal recessive severe combined immunodeficiency caused by defects of the Jak3 tyrosine kinase

Defects of the common gamma chain subunit of the cytokine receptors (gamma(c)) or of Jak3, a tyrosine kinase required for gamma(c) signal transduction, result in T-B+ severe combined immunodeficiency (SCID). However, atypical cases, characterized by progressive development of T lymphocytes, have been also reported. We describe a child with SCID caused by Jak3 gene defects, which strongly but not completely affect Jak3 protein expression and function, who developed a substantial number (>3,000/mu L) of autologous CD3(+)CD4(+) T cells. These cells showed a primed/activated phenotype (CD45R0(+) Fas(+) HLA-DR+ CD62L (lo)). defective secretion of T-helper 1 and T-helper 2 cytokines, reduced proliferation to mitogens, and a high in vitro susceptibility to spontaneous (caused by downregulation of bcl-2 expression) as well as activation-induced cell death. A restricted T-cell receptor repertoire was observed, with oligoclonal expansion within each of the dominant segments. These features resemble those observed in gamma(c)(-/y) and in Jak3(-/-) mice, in which a population of activated, anergic T cells (predominantly CD4(+)) also develops with age. These results suggest that residual Jak3 expression and function or other Jak3-independent signals may also permit the generation of CD4(+) T cells that undergo in vivo clonal expansion in humans; however, these mechanisms do not allow development of CD8(+) T cells, nor do they fully restore the functional properties of CD4(+) T lymphocytes. (C) 1998 by The American Society of Hematology.