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
Duilio Brugnoni,
Luigi D. Notarangelo,
Alessandra Sottini,
Paolo Airò,
Marta Pennacchio,
Evelina Mazzolari,
Simona Signorini,
Fabio Candotti,
Anna Villa,
Patrizia Mella,
Paolo Vezzoni,
Roberto Cattaneo,
Alberto G. Ugazio, and
Luisa Imberti
From the Servizio di Immunologia Clinica, Clinica Pediatrica,
Consorzio per le Biotecnologie, III Laboratorio Analisi, Spedali
Civili, Brescia; and Istituto di Tecnologie Biomediche Avanzate, CNR,
Milano, Italy.
Defects of the common gamma chain subunit of the cytokine receptors
(
c) or of Jak3, a tyrosine kinase required for
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/µL) of autologous
CD3+CD4+ T cells. These cells showed a
primed/activated phenotype (CD45R0+ Fas+
HLA-DR+ CD62Llo), 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
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.
Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 949-955
© 1998 by The American Society of Hematology.
