13-3 Defects in T-cell development can result in severe combined immunodeficiencies.
The developmental pathways leading to circulating naive T cells and B cells are summarized in Fig. 13.2. Patients with defects in Tcell development are highly susceptible to a broad range of infectious agents. This demonstrates the central role of Tcell differentiation and maturation in adaptive immune responses to virtually all antigens. Because such patients exhibit neither Tcelldependent antibody responses nor cellmediated immune responses, and thus cannot develop immunological memory, they are said to suffer from severe combined immunodeficiency (SCID).
Xlinked SCID (XSCID) is the most frequent form of SCID and is caused by mutations in the gene IL2RG on the human X chromosome, which encodes the interleukin2 receptor (IL2R) common gamma chain (γc). γc is required in all receptors of the IL2 cytokine family (IL2, IL4, IL7, IL9, IL15, and IL21). Patients with XSCID thus have defects in signaling of all IL2family cytokines, and, owing to the defects in IL7 and IL15, their T cells and NK cells fail to develop normally (see Fig. 13.2). Bcell numbers, on the other hand, are normal, but due to absence of Tcell help, their function is not. XSCID patients are overwhelmingly male; in females who are carriers of the mutation, Tcell and NKcell progenitors in which Xinactivation has preserved the wildtype IL2RG allele progress through development to establish a normal mature immune repertoire. XSCID is known as the ‘bubble boy disease’ after a boy with XSCID who lived in a protective bubble for more than a decade before he died from complications of a bone marrow transplant. A clinically and immunologically indistinguishable type of SCID is associated with an inactivating mutation in the kinase Jak3 (see Section 81), which physically associates with γc and transduces signaling through γcchain cytokine receptors. This autosomal recessive mutation also impairs the development of T and NK cells, but the development of B cells is unaffected.
Other immunodeficiencies in mice have pinpointed more precisely the roles of individual cytokines and their receptors in Tcell and NKcell development. For example, mice with targeted mutations in the βc gene (IL2RB) defined a key role for IL15 as a growth factor for the development of NK cells, as well as
Fig. 13.1 Human immunodeficiency syndromes. the specific gene defect, the consequence for the immune system, and the resulting disease susceptibilities are listed for some common and some rare human immunodeficiency syndromes. Severe combined immunodeficiency (SCiD) can be due to many different defects, as summarized in Fig. 13.2 and described in the text. aiD, activation-induced cytidine deaminase; atM, ataxia telangiectasiamutated protein; eBV, epstein–Barr virus; iKK, inhibitor of κ B kinase; Stat3, signal transducer and activator of transcription 3; taP, transporters associated with antigen processing; unG, uracil-Dna glycosylase.
a role for the cytokine in Tcell maturation and trafficking. Mice with targeted mutations in IL15 itself or the α chain of its receptor also have no NK cells and relatively normal Tcell development, but they show a more specific Tcell defect, primarily limited to impaired maintenance of memory CD8 T cells.