Absence or defective function of Janus kinase 3 (JAK3) causes one of several defined variants of severe combined immune deficiency (SCID),1 a disorder that is fatal in infancy unless treated by hematopoetic stem cell transplantation (HSCT).2 JAK3 is the only member of the Janus family of intracellular protein tyrosine kinases primarily expressed in hematopoetic cells, and by associating with the common gamma chain it is essential for effective cytokine signal transduction and, thus, the regulation of lymphocyte differentiation and function.3 Besides its pathogenic role in SCID, JAK3 has become a target for inhibition by designed drugs representing a highly promising approach for immunosuppression in organ transplantation.4
In this issue of Blood, Roberts and colleagues (page 2009) further define the molecular genesis of SCID arising from abnormalities of JAK3. The authors performed a detailed study, including a description of the long-term outcomes of HSCT to treat the disease, in 10 affected individuals from 7 unrelated North American families. Mutations in patients always resulted in abnormal JAK3-dependent, interleukin 2 (IL-2)–induced signal transducer and activator of transcription-5 (STAT5) phosphorylation, even if mutations allowed expression of dysfunctional proteins, clearly indicating disease-causing roles for these mutations. Of interest, in one patient with complete absence of JAK3 protein, no mutation was found in spite of extensive and detailed sequence analysis, suggesting the possibility of a mutation of distant JAK3 regulatory elements. Mutational analysis, while representing an important tool in the exact evaluation of the underlying mechanism causing SCID, may not necessarily be helpful in the recognition and diagnosis of this devastating disease in those special cases.
Treatment in the majority of studied patients consisted of infusion of T-cell–depleted marrow cells from human leukocyte antigen (HLA) nonidentical parents. In 5 of 8 patients, this treatment resulted in long-term reconstitution of T-cell immunity by parental donor cells, but not of B-cell and natural killer (NK)–cell functions, which always failed to develop. Similar outcomes with immune reconstitution remaining restricted to T-cell immunity are also observed in patients with other SCID variants when such patients undergo this procedure in the absence of preparative cytoreductive conditioning prior to infusion of T-cell–depleted stem cells.2 Does this outcome reflect the failure of permanent engraftment of early lymphoid precursor cells from which B and NK cells also arise? If so, why is a T-cell system being permanently established? Is donor cell engraftment restricted to the thymus? Indeed, in nonconditioned patients with SCID who had functioning T-cell systems after HSCT, no donor CD34+ marrow cells were observed.5 Donor precursor cells may immigrate into the thymic organ at the time of transplantation, allowing T-cell maturation and establishment of a functioning peripheral T-cell system. If the influx of precursors into the thymus is indeed time-restricted, the question of the long-term stability of thymic functions in these patients with SCID is relevant. The use of conditioning, as applied in the study by Roberts et al in a patient who underwent a second HSCT from an unrelated cord blood donor, led to full immunologic reconstitution by donor T, B, and NK cells. This outcome likely reflects establishment of a cellular graft at an early precursor cell level and may also represent an advantage for the long-term function of the thymus, where seeding by pre-T cells of the organ from the engrafted precursor cell pool likely continues. JAK3 deficiency and its treatment by HSCT thus serve as useful models to dissect reconstitution of the immune system and to develop effective modifications of HSCT.
