Humans with a deficiency of the IL7 receptor α chain have no T cells but normal levels of NK cells, illustrating that IL7 signaling, while essential for Tcell development, is not essential for the development of NK cells (see Fig. 13.2). Interestingly, mice with a genetargeted deficiency of the IL7R share with humans a deficiency of T cells, but also lack B cells, which is not the case in humans. This illustrates the speciesspecific role of certain cytokines, and provides a cautionary note against extrapolating findings from mice to humans. In humans and mice whose T cells show defective production of IL2 after receptor stimulation, most Tcell development itself is normal, although there is impaired development of FoxP3+ Treg cells that predisposes to immuneregulatory abnormalities and autoimmunity (see Chapter 15). The more limited effects of individual cytokine signaling defects are in contrast to the global defects in T and NKcell development in patients with XSCID.
TCRpre-TCR CD8 CD4 pro-T cell pro-B cell pre-B cell immature B cell B1 B cell natural killer cell B2 B cell MZ B cell pro-NK CLPHSC pre-T cell double-positive T cell CD8 T cell thymus Bone marrow CD4 T cell CD8 T cell CD4 T cell pre-BCR BCR IgD CD3˜, CD3°, CD3˛TAP1, TAP2, tapasin CIITA, RFXANK, RFX5, RFXAP ˝H, ˙5, Igˆ, IgˇBLNK ZAP-70 AIRERAG-1, RAG-2 Artemis, DNA-PKc, DNA ligase IV CD45 BTK IL-7RˆADA Periphery ˇc, Jak3 °c SCID SCID XSCID MHC class I defciency MHC class II defciency B-cell defciency B-cell defciency SCID-like immunodefciency APECEDSCID Omenn syndrome RS-SCID SCID SCID SCID X-linked agammaglobulinemia Fig. 13.2 Defects in T-cell and B-cell development that cause immunodeficiency. the pathways leading to circulating naive t cells and B cells are shown here. Mutations in genes that encode the proteins (indicated in red boxes) are known to cause human immunodeficiency diseases. BCR, B-cell receptor; ClP, common lymphoid progenitor; HSC, hematopoietic stem cell; MZ B cell, marginal zone B cell; pre-BCR, pre-B-cell receptor; pre-tCR, pre-t-cell receptor; RS-SCiD, radiation-sensitive SCiD; SCiD, severe combined immunodeficiency; tCR, t-cell receptor; XSCiD, X-linked SCiD. immunodeficiency can also be caused by mutations in genes in the thymic epithelium that impair thymic development, and thus t-cell development.
As in all serious Tcell deficiencies, patients with XSCID do not make effective antibody responses to most antigens, although their B cells seem normal. Most, but not all, naive IgMpositive B cells from female carriers of XSCID have inactivated the defective X chromosome rather than the normal one (see Section 133), showing that Bcell development is affected by, but is not wholly dependent on, the γc chain. Mature memory B cells that have undergone class switching have inactivated the defective X chromosome almost without exception. This might reflect the fact that the γc chain is also part of the receptor for IL21, which is important for the maturation of classswitched B cells (see Section 104).
13-4 SCID can also be due to defects in the purine salvage pathway.