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Dependence of lymphopenia-induced T cell proliferation on the abundance of peptide/ MHC epitopes and strength of their interaction with T cell receptors.

Factors that affect naive T cell proliferation in syngeneic lymphopenic hosts were investigated. 2C T cell receptor (TCR) transgenic T cells lacking both CD8 and CD4 survived but hardly proliferated. Proliferation of CD8(+) 2C cells was proportional to the abundance of cognate peptide/MHC complexes and was severely inhibited by injection of anti-CD8 antibody. Weakly reactive self-peptides slightly enhanced CD8(+) 2C cell proliferation whereas a potent agonist peptide promoted much more rapid proliferation, but inflammation-stimulating adjuvant had only a small effect on the rate of cell proliferation. The findings suggest that under uniform lymphopenic conditions, the widely different rates of proliferation of T cells expressing various TCR, or the same TCR in the presence or absence of CD8, reflect the strength of interaction between TCR and MHC associated with particular self-peptides.

Animals↗

Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine.

Interleukin (IL)-7 is a potent stimulus for immature T and B cells and, to a lesser extent, mature T cells. We have inactivated the IL-7 gene in the mouse germline by using gene-targeting techniques to further understand the biology of IL-7. Mutant mice were highly lymphopenic in the peripheral blood and lymphoid organs. Bone marrow B lymphopoiesis was blocked at the transition from pro-B to pre-B cells. Thymic cellularity was reduced 20-fold, but retained normal distribution of CD4 and CD8. Splenic T cellularity was reduced 10-fold. Splenic B cells, also reduced in number, showed an abnormal population of immature B cells in adult animals. The remaining splenic populations of lymphocytes showed normal responsiveness to mitogenic stimuli. These data show that proper T and B cell development is dependent on IL-7. The IL-7-deficient mice are the first example of single cytokine-deficient mice that exhibit severe lymphoid abnormalities.

Animals↗

IL-2 therapy and thymic production of naive CD4 T cells in HIV-infected patients with severe CD4 lymphopenia.

OBJECTIVES: IL-2 therapy increases memory and naive CD4 T cells in HIV-infected patients, but its effect on thymopoiesis is unknown. To investigate this effect, we quantified T-cell receptor rearrangement excision circles (TREC) in CD4 T cells from lymphopenic AIDS patients treated with highly active antiretroviral therapy and IL-2. METHODS: CD4 cell subsets were evaluated by flow cytometry using anti-CD45RO/RA, CD62L, Ki67 and CD95 monoclonal antibodies. The proportion of recent thymic emigrant had been quantified by a real-time polymerase chain reaction assay for signal joint TREC in peripheral blood mononuclear and purified CD4 T cells. RESULTS: At initiation of IL-2, TREC copies/microl of blood were correlated with naive T cell numbers and age. Both naive and TREC numbers/microl significantly increased over time in all patients, with a wide range of TREC increases. Higher percentages of CD4+CD45RO-negative cells positive for the Ki67 cell-cycle marker were found in patients with a low TREC increase, but remained stable under IL-2. TREC and naive cell recovery were correlated; they also correlated with the numbers of TREC and naive cells at the start of IL-2, and with age, suggesting a thymic origin for naive T-cell recovery. A mathematical model showing the linear recovery of naive cells and TREC under IL-2 also strongly suggested that a naive T-cell increase reflects thymic export and involves little net death and proliferation. CONCLUSION: Although we cannot rule out a mechanism of altered proliferation or death rate, the thymus plays an important role in the long-term recovery of naive T cells under IL-2 therapy.

Adult↗

Risk factors for CD4 lymphopenia in patients treated with a tenofovir/didanosine high dose-containing highly active antiretroviral therapy regimen.

In this study, the dynamics of CD4 cell depletion during tenofovir/didanosine co-administration were analysed. Ninety-five HIV-positive patients were followed for 562 days, and 37 lost at least 50 CD4 cells, with a median delay of 274 days. Cox analysis showed that the CD4 cell decrease was associated with a duration of treatment by didanosine of more than 853 days and a didanosine dose of more than 5.50 mg/kg.

Adenine↗

CD4 cell lymphopenia and atherosclerosis in renal transplant recipients.

Several animal studies suggest that T cell-mediated immunodeficiency may play a role in the progression of atherosclerosis. This study examined the association between lymphocyte subsets and atherosclerotic events in renal transplant recipients. A total of 302 consecutive renal transplant recipients were enrolled in this prospective study. Peripheral blood lymphocyte subsets were quantified and analyzed with respect to other known cardiovascular risk factors. The patients were followed for a mean duration of 23.5 +/- 4.5 mo. Mean CD4, CD8, and CD19 cell levels were 511 +/- 290/mm(3), 553 +/- 596/mm(3), and 66 +/- 62/mm(3), respectively. CD4 levels were positively related to transplant duration (r = 0.32; P = 0.02) and inversely related to age (r = 0.35; P = 0.01). Twenty-five atherosclerotic events (AE) occurred in 25 patients (8.3%). CD4 levels were lower in patients who experienced CVE (288 +/- 170/mm(3) versus 531 +/- 290/mm(3); P < 0.0001). Cox regression analysis showed that patients in the three upper quartiles of CD4 cell count had a decreased risk of CVE compared with those in the lowest quartile. There was a linear increase in risk of CVE with decreasing CD4 cell count (P < 0.0001). A CD4 cell count in the highest quartile (>663/mm(3)) divided the risk of CVE by 10 as compared with the lowest quartile. In conclusion, CD4 lymphocytopenia is an independent risk factor for the development of cardiovascular complications in renal transplant recipients, suggesting that impaired immune response promotes accelerated atherogenesis in this population.

Adult↗

A novel mutation in the interleukin-2 receptor gamma gene as the cause of lymphopenia in a neonate vertically exposed to human immunodeficiency virus.

Perinatal transmission prophylaxis has led to a significant reduction of vertical human immunodeficiency virus (HIV) infection. Antiretroviral drugs are being widely used before and during pregnancy, although these drugs can have possible adverse effects on the fetus and newborn. In this context, we report a unique case of X-linked severe combined immunodeficiency in a neonate vertically exposed to HIV.

Adult↗

Idiopathic CD4+ T lymphopenia in older persons.

OBJECTIVE: Survey of the association of idiopathic CD4+ T cell lymphocytopenia in older persons with protein energy undernutrition and unusual infections/colonizations. METHOD: Retrospective chart analysis. RESULTS: Five subjects aged 61 to 87 years, with unusual organisms and/or either marasmus or kwashiorkor, were noted to have absolute CD4+ and CD8+ T cell lymphocytopenia. All were HIV negative. CONCLUSION: T cell lymphocytopenia may not be a uncommon finding in malnourished older persons, but additional studies to determine its prevalence need to be undertaken. Its role in disease and impact on therapeutic response needs to be further explored.

Age Factors↗