IntroductionHuman cytomegalovirus (CMV) is a widespread ␤-herpes virus that infects more than half of the Western population. Primary infection induces a life-long latent infection in the immunocompetent host with asymptomatic episodes of viral replication, which are controlled by a vigorous immune response. CMV infection is responsible for increased morbidity and mortality after allogeneic stem cell transplantation (SCT) as either CMV reactivation in CMV-seropositive patients or primary infection in CMV-seronegative patients receiving grafts from seropositive donors. Several studies have demonstrated a significant decline in a overall survival in human leukocyte antigen-identical sibling transplantations or in unrelated transplantations where either the donor or the patient was CMV-seropositive. 1,2 The central mechanism controlling CMV infection is mediated by antigen-specific CD8 ϩ cytotoxic and CD4 ϩ ␣␤ T lymphocytes and natural killer (NK) cells. [3][4][5] CMV-specific CD3 ϩ CD8 ϩ CD28 Ϫ CD57 ϩ ␣␤ T cells are regarded as the principle effector cells controlling CMV reactivation. 6,7 Both humoral and cellular immunity is involved in protective immune responses to CMV reactivation and CMV resolution. 8 Recent interest has focused on ␥␦ T cells and their role in immune responses during CMV infection. ␥␦ T cells are often termed the "unconventional" T cells and represent a minor population of circulating T cells (Ͻ 5%) in humans but are present in large numbers in epithelial tissues. [9][10][11][12][13] In contrast to ␣␤ T cells, which recognize peptides bound to major histocompatibility complex (MHC) class I or class II molecules, most ␥␦ T cells lack surface expression of CD4 or CD8 and display a non-MHC-restricted recognition. 14,15 There are 2 major subsets of ␥␦ T cells present in human peripheral blood: a subset of ␥␦ T cells expressing a T-cell receptor (TCR) encoded by the V␦2 and V␥9 gene segments, which accounts for 50% to 90% of ␥␦ T cells in adult peripheral blood and a minor V␦1 subset more frequent at mucosal epithelium sites, such as skin and the intestine. An additional small subset of V␦3 ␥␦ T cells is also present in peripheral blood but represents a minor population of less than 0.1% of CD3 ϩ T cells. The ␥␦ T cells recognize ligands that are not seen by ␣␤ T cells and provide additional means by which the immune system can maintain local immunosurveillance with immediate tumor defense, selective recognition of viral antigens, and bacterial metabolites. 12,14 V␦1 ␥␦ T cells recognize ligands for an activating receptor NKG2D, such as MHC class I-related chain A (MICA and MICB) stress-induced antigens expressed on epithelial tumor cells, some leukemias, lymphomas, and the UL16-binding proteins. [16][17][18][19][20][21][22][23][24] V␦2 ␥␦ T cells recognize low molecular weight nonpeptidic phosphoantigens, particularly intermediates of the nonmevalonate pathway of bacterial isoprenoid biosynthesis 25 or isopenthenyl pyrophosphate and aminobiphosphonates in eukaryotic cells. 26 Recent studies have...

The immune suppression inherent in allogeneic stem cell transplantation (SCT) offers a favorable environment for infection by opportunistic agents, such as human cytomegalovirus (CMV). Despite the application of potent antiviral prophylaxis, patients remain at risk for CMV infection until adequate immunity is restored. CMV-specific CD8(+) T cell counts were monitored, using HLA-A2 tetrameric complexes, to establish the level of immune response to the viral phosphoprotein UL83 in patients after allogeneic SCT. Correlating this with viral replication and clinical status shows that the level of tetramer-positive T cells provides an assessment of CMV immune reconstitution after stem cell transplantation. Most patients with seropositive donors did reconstitute long-term CMV immunity, unless prolonged immunosuppression to control graft-versus-host disease was induced. Together with polymerase chain reaction testing, this technique provides measurable parameters that can be a guide to therapeutic decision making and can form the basis of CMV immunotherapy.

Key Points Allo-HSCT with RIC is safe and effective in younger adults with severe PID. Referral triggers should include severe infections, autoimmunity, malignancy, and disease progression despite conservative management.

Until recently, hematopoietic stem cell transplantation was the only curative option for Wiskott-Aldrich syndrome (WAS). The first attempts at gene therapy for WAS using a ϒ-retroviral vector improved immunological parameters substantially but were complicated by acute leukemia as a result of insertional mutagenesis in a high proportion of patients. More recently, treatment of children with a state-of-the-art self-inactivating lentiviral vector (LV-w1.6 WASp) has resulted in significant clinical benefit without inducing selection of clones harboring integrations near oncogenes. Here, we describe a case of a presplenectomized 30-year-old patient with severe WAS manifesting as cutaneous vasculitis, inflammatory arthropathy, intermittent polyclonal lymphoproliferation, and significant chronic kidney disease and requiring long-term immunosuppressive treatment. Following reduced-intensity conditioning, there was rapid engraftment and expansion of a polyclonal pool of transgene-positive functional T cells and sustained gene marking in myeloid and B-cell lineages up to 20 months of observation. The patient was able to discontinue immunosuppression and exogenous immunoglobulin support, with improvement in vasculitic disease and proinflammatory markers. Autologous gene therapy using a lentiviral vector is a viable strategy for adult WAS patients with severe chronic disease complications and for whom an allogeneic procedure could present an unacceptable risk. This trial was registered at www.clinicaltrials.gov as #NCT01347242.