Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling

Abstract

Adenosine deaminase (ADA) deficiency in humans results in a severe combined immunodeficiency (SCID). This immunodeficiency is associated with severe disturbances in purine metabolism that are thought to mediate lymphotoxicity. The recent generation of ADA-deficient (ADA -/-) mice has enabled the in vivo examination of mechanisms that may underlie the SCID resulting from ADA deficiency. We demonstrate severe depletion of T and B lymphocytes and defects in T and B cell development in ADA -/-mice. T cell apoptosis was abundant in thymi of ADA -/-mice, but no increase in apoptosis was detected in the spleen and lymph nodes of these animals, suggesting that the defect is specific to developing thymocytes. Studies of mature T cells recovered from spleens of ADA -/-mice revealed that ADA deficiency is accompanied by TCR activation defects of T cells in vivo. Furthermore, ex vivo experiments on ADA -/-T cells demonstrated that elevated adenosine is responsible for this abnormal TCR signaling. These findings suggest that the metabolic disturbances seen in ADA -/-mice affect various signaling pathways that regulate thymocyte survival and function. Experiments with thymocytes ex vivo confirmed that ADA deficiency reduces tyrosine phosphorylation of TCRassociated signaling molecules and blocks TCR-triggered calcium increases.

Reduced thymic output, increased spontaneous apoptosis and oligoclonal B cells in polyethylene glycol-adenosine deaminase-treated patients

“…dATP accumulation interferes with DNA replication and notably can promote apoptosis by stimulating "apoptosome" assembly through the formation of a specific complex containing dATP, cytoplasmic cytochrome c, Apaf-1, and caspase 9 [32][33][34] . Experiments performed in ADA-deficient mice and in murine fetal thymic organ culture indicate that apoptosis is an important component of disease pathogenesis [24,35]. Although we did not observe "active problems" at the time of Annexin V measurement that could have influenced the results, we found a significant number of cells in an early stage of apoptosis, suggesting that this can be a mechanism contributing to the T cell lymphopenia observed in our ADA-SCID patients treated with PEG-ADA.…”

Impaired Germinal Center Maturation in Adenosine Deaminase Deficiency

“…In line with our B cell findings, other studies have shown proliferation and activation signaling defects in T cells under conditions of ADA deficiency. For instance, ADA-deficient peripheral T cells have shown a reduction of tyrosine phosphorylation of TCR-associated signaling molecules and a block of TCRmediated calcium flux (17). Also, extracellular adenine nucleotides, which accumulate in ADA deficiency, inhibit CD4 ϩ T cell activation via an increase in cAMP induced by an unidentified purinergic receptor (29).…”

“…An investigation of the B cell compartment in the bone marrow of ADA-deficient mice was initiated to determine whether, in analogy to T cell development, a blockade in B cell lymphopoiesis exists (5,16,17). The developmental parallels showed by B and T cells, including gene rearrangement and selection, suggested that ADA deficiency, with a block in early T cell development, could equally affect the early B cell maturation program.…”

High Levels of Adenosine Deaminase on Dendritic Cells Promote Autoreactive T Cell Activation and Diabetes in Nonobese Diabetic Mice

“…In the initial article by Apasov et al (27), ADA deficiency without PEG-ADA injection showed greater thymic apoptosis with a relatively normal peripheral lymphocyte distribution. To characterize any potential immunological defects with the maintenance of PEG-ADA, 4-wk-old thymic and splenic populations were analyzed for T and B cell markers.…”