Mutations of the Janus kinase 3 (JAK3) have been previously described to cause an autosomal recessive variant of severe combined immunodeficiency (SCID) usually characterized by the near absence of T and NK cells, but preserved numbers of B lymphocytes (T-B+SCID). We now report a family whose JAK3 mutations are associated with the persistence of circulating T cells, resulting in previously undescribed clinical presentations, ranging from a nearly unaffected 18-year-old subject to an 8-year-old sibling with a severe lymphoproliferative disorder. Both siblings were found to be compound heterozygotes for the same deleterious JAK3 mutations: an A96G initiation start site mutation, resulting in a dysfunctional, truncated protein product and a G2775(+3)C mutation in the splice donor site sequence of intron 18, resulting in a splicing defect and a predicted premature stop. These mutations were compatible with minimal amounts of functional JAK3 expression, leading to defective cytokine-dependent signaling. Activated T cells in these patients failed to express Fas ligand (FasL) in response to IL-2, which may explain the accumulation of T cells with an activated phenotype and a skewed T cell receptor (TcR) Vbeta family distribution. We speculate that residual JAK3 activity accounted for the maturation of thymocytes, but was insufficient to sustain IL-2-mediated homeostasis of peripheral T cells via Fas/FasL interactions. These data demonstrate that the clinical spectrum of JAK3 deficiency is quite broad and includes immunodeficient patients with accumulation of activated T cells, and indicate an essential role for JAK3 in the homeostasis of peripheral T cells in humans.

Summary:The effect of mixed chimerism on the pace of post-transplant immune reconstitution is unknown. Using flow cytometry, recall and neo-antigen vaccine responses, and T cell receptor recombination excision circle (TREC) quantification, we evaluated phenotypic and functional characteristics of T and B cells in nine patients following non-myeloablative, HLA-identical peripheral blood stem cell transplantation for chronic granulomatous disease. Engraftment of T cell, B cell, and myeloid lineages proceeded at similar paces within each patient, but engraftment kinetics segregated patients into two groups: adults, who became full donor T cell chimeras before 6 months (rapid engrafters) and children, who became full donor T cell chimeras after 6 months or not at all (slow engrafters). Quantitative B cell recovery was achieved by 6 weeks after transplantation in children, but was delayed until 1 year in adults. a lack of response to routine vaccinations and an increased incidence of opportunistic infections. [1][2][3][4] This dysfunction is a consequence of quantitative and qualitative defects in both the cellular and humoral arms of the immune system.Quantitative defects of the immune system after T celldepleted transplantation are characterized by varying periods of sub-normal lymphocyte subset counts. NK cells recover within 3 months after transplantation, followed by CD8 + T cells, and lastly by B cells and CD4 + T cells. 5-10Naive T cell recovery, which is important for the restoration of a normal T cell repertoire, is inversely proportional to age. [11][12][13][14][15][16] Correlating with naive T cell recovery is the fact that children respond more quickly than adults to vaccination with recall antigens after transplantation. 17Quantitative humoral defects after myeloablative transplantation include IgA, IgM, and IgG subclass deficiencies.18-21 In addition, reconstituted Ig concentrations do not necessarily coincide with functional humoral immunity. 22Opportunistic infections during the post-transplant period contribute significantly to the morbidity and mortality of this procedure. The incidence of opportunistic infections is proportional to the degree of T cell depletion. Use of less intensive non-myeloablative marrow conditioning regimens has reduced the conditioning-related toxicity, 23,24 but the effects on post-transplant immune recovery have not been studied in detail. Evidence of more rapid recovery of immune function following non-myeloablative allogeneic stem cell transplantation would further enhance the appeal of this approach.The patients in this study were being treated for chronic granulomatous disease (CGD) with an allogeneic, nonmyeloablative, T cell-depleted, hematopoietic stem cell transplant using an HLA-identical sibling donor. 25 This approach allowed for the unique opportunity to study immune reconstitution in the setting of mixed hematopoietic chimerism. Analysis of several quantitative and qualitative measures of immune reconstitution in this homogeneous group of patients reveals diff...