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Thymic hypoplasia is a frequent feature of the 22q11.2 deletion syndrome, but we know little about patients' age-related thymic output and long-term consequences for their immune system. We measured the expression of T cell receptor rearrangement excision circles (TREC) and used flow cytometry for direct subtyping of recent thymic emigrant (RTE)-related T cells in 43 patients (aged 1–54 years; median 9 years) from all over Norway and in age-matched healthy controls. Thymic volumes were estimated by ultrasound in patients. TREC levels correlated well with RTE-related T cells defined by co-expression of CD3, CD45RA and CCR9 ( r = 0·84) as well as with the CD4+ and CD8+ T cell subtypes. RTE-related T cell counts also paralleled age-related TREC reductions. CD45RA+ T cells correlated well with absolute counts of CD4+ ( r = 0·87) and CD8+ ( r = 0·75) RTE-related T cells. Apart from CD45RA- T cells, all T cell subsets were lower in patients than in controls. Thymic volumes correlated better with RTE-related cells ( r = 0·46) than with TREC levels ( r = 0·38). RTE-related T cells and TREC levels also correlated well ( r = 0·88) in patients without an identifiable thymus. Production of RTEs is impaired in patients with a 22q11.2 deletion, and CCR9 appears to be a good marker for RTE-related T cells. [ABSTRACT FROM AUTHOR]

A subgroup of patients with 22q11·2 microdeletion and partial DiGeorge syndrome (pDGS) appears to be susceptible to non-cardiac mortality (NCM) despite sufficient overall CD4+ T cells. To detect these patients, 20 newborns with 22q11·2 microdeletion and congenital heart disease were followed prospectively for 6 years. Besides detailed clinical assessment, longitudinal monitoring of naive CD4+ and cytotoxic CD3+CD8+ T cells (CTL) was performed. To monitor thymic activity, we analysed naive platelet endothelial cell adhesion molecule-1 (CD31+) expressing CD45RA+RO-CD4+ cells containing high numbers of T cell receptor excision circle (TREC)-bearing lymphocytes and compared them with normal values of healthy children ( n = 75). Comparing two age periods, low overall CD4+ and naive CD4+ T cell numbers were observed in 65%/75%, respectively, of patients in period A (< 1 year) declining to 22%/50%, respectively, of patients in period B (> 1/< 7 years). The percentage of patients with low CTLs (< P10) remained robust until school age (period A: 60%; period B: 50%). Low numbers of CTLs were associated with abnormally low naive CD45RA+RO-CD4+ T cells. A high-risk (HR) group ( n = 11) and a standard-risk (SR) ( n = 9) group were identified. HR patients were characterized by low numbers of both naive CD4+ and CTLs and were prone to lethal infectious and lymphoproliferative complications (NCM: four of 11; cardiac mortality: one of 11) while SR patients were not (NCM: none of nine; cardiac mortality: two of nine). Naive CD31+CD45RA+RO-CD4+, naive CD45RA+RO-CD4+ T cells as well as TRECs/106 mononuclear cells were abnormally low in HR and normal in SR patients. Longitudinal monitoring of naive CD4+ and cytotoxic T cells may help to discriminate pDGS patients at increased risk for NCM. [ABSTRACT FROM AUTHOR]

Chromosome 22q11.2 deletion syndrome is a common disorder characterized by thymic hypoplasia, conotruncal cardiac defect and hypoparathyroidism. Patients have a risk of infections and autoimmunity associated with T lymphocytopenia. To assess the immunological constitution of patients, the numerical changes and cytokine profile of circulating T cells were analysed by flow cytometry and real-time polymerase chain reaction (PCR). CD3+, CD4+, T cell receptor (TCR)αβ+ or CD8αα+ cell counts were lower, and CD56+ cell counts were higher in patients than in controls during the period from birth to adulthood. The ageing decline of CD3+ or CD4+ cell counts was slower in patients than in controls. The proportion of CD8αα+ cells increased in controls, and the slope index was larger than in patients. On the other hand, both the number and proportion of Vα24+ cells increased in patients, and the slope indexes tended to be larger than in controls. The positive correlation of the number of T cells with CD8αα+ cells was observed only in patients, and that with Vα24+ cells was seen only in controls. No gene expression levels of interferon (IFN)-γ, interleukin (IL)-10, transforming growth factor (TGF)-β, cytotoxic T lymphocyte antigen 4 (CTLA4) or forkhead box p3 (Foxp3) in T cells differed between patients and controls. There was no significant association between the lymphocyte subsets or gene expression levels and clinical phenotype including the types of cardiac disease, hypocalcaemia and frequency of infection. These results indicated that T-lymphocytopenia in 22q11.2 deletion patients became less severe with age under the altered composition of minor subsets. The balanced cytokine profile in the limited T cell pool may represent a T cell homeostasis in thymic deficiency syndrome. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine whether increased apoptosis in peripheral blood lymphocytes plays a role in T cell deficiency associated with DiGeorge anomaly. T cell subsets from a patient with DiGeorge anomaly were examined for the expression of Fas, FasL, Bcl-2 and Bcl-XL at the protein level with monoclonal antibodies, using dual-colour flow cytometry, and at the mRNA level in mononuclear cells by quantitative reverse transcriptase-polymerase chain reaction. In vitro spontaneous apoptosis was examined by propidium iodide staining and DNA fragmentation, using flow cytometry and gel electrophoresis, respectively. Fas and FasL expression, both at the level of protein and of mRNA, was increased, whereas Bcl-2 expression was decreased both at the level of protein and of mRNA. However, no difference in Bcl-XL expression was observed between the patient and an age-matched control. A significant proportion of both CD4+ and CD8+ T cells from the patients underwent spontaneous apoptosis, whereas almost no spontaneous apoptosis was observed in the age-matched control. These data suggest that spontaneous apoptosis in T lymphocytes, at least in part, may be responsible for T cell deficiency in DiGeorge anomaly. [ABSTRACT FROM AUTHOR]