The Bare Lymphocyte Syndrome and Other Defects in T Cell Positive Selection

The generation of single-positive CD4+ and CD8+ T cells from double-positive thymocytes depends on positive selection and lineage commitment events. Specific inherited mutations in genes that regulate the process of positive selection abrogate the development of CD4+ T cells or of CD8+ T cells.

Class II major histocompatibility complex (MHC) deficiency, also called bare lymphocyte syndrome, is a rare heterogeneous group of autosomal recessive diseases in which patients express little or no HLA-DP, HLA-DQ, or HLA-DR on B lymphocytes, macrophages, and dendritic cells and fail to express class II MHC molecules in response to IFN-y. They express normal or only slightly reduced levels of class I MHC molecules and p2-microglobulin. Most cases of the bare lymphocyte syndrome are due to mutations in genes encoding proteins that regulate class II MHC gene transcription. For example, mutations affecting the constitutively expressed transcription factor

RFX5 or the IFN-y-inducible transcriptional activator CIITA lead to reduced class II MHC expression and a failure of APCs to activate CD4+ T lymphocytes. Failure of antigen presentation may result in defective positive selection of T cells in the thymus, with a reduction in the number of mature CD4+ T cells or defective activation of cells in the periphery. Affected individuals are deficient in DTH responses and in antibody responses to T cell-dependent protein antigens. The disease appears within the first year of life and is usually fatal unless it is treated by bone marrow transplantation.

Autosomal recessive class I MHC deficiencies have also been described and are characterized by decreased CD8+ T cell numbers and function. In some cases, the failure to express class I MHC molecules is due to mutations in the TAP-1 or TAP-2 genes, which encode the subunits of the TAP (transporter associated with antigen processing) complex, which normally transports peptides from the cytosol into the endoplasmic reticulum, where they are required for class I MHC assembly (see Chapter 6). These TAP-deficient patients express few cell surface class I MHC molecules, a phenotype similar to TAP gene knockout mice. Such patients suffer mainly from necrotizing granulomatous skin lesions and respiratory tract bacterial infections, but not viral infections, which is surprising considering that a principal function of CD8+ T cells is defense against viruses. A similar deficiency of class I MHC expression has been observed in patients with mutations in the gene encoding the tapasin protein (see Chapter 6).

Patients with ZAP-70 deficiency have a lineage commitment defect resulting in reduced CD8+ T cells but not CD4+ T cells; the reason for the selective loss is not clear. This specific tyrosine kinase defect does not compromise CD4 + T cell development or emigration to the periphery. However, these CD4+ T cells fail to proliferate normally when challenged with antigens.

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