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Background & Aims: Regulatory CD25+ T cells (Treg) are effective in the prevention and down-regulation of inflammatory bowel disease (IBD) in animal models. Functional Treg cells are characterized by the expression of the transcription factor FOXP3 and show a CD4+CD25high phenotype in humans. The aim of this study was to determine whether disease activity in IBD correlates with changes in frequency of Treg cells and their distribution in the intestinal mucosa. Methods: Treg cells were analyzed from peripheral blood and from biopsy specimens of IBD patients, inflammatory controls, and healthy volunteers by flow cytometry (CD4+CD25high), immunochemistry (FOXP3), and real-time PCR (FOXP3). Regulatory properties of purified peripheral CD4+CD25high Treg cells were determined by their suppressive effect on the proliferation of CD4+CD25− T cells. Results: In peripheral blood, CD4+CD25high T cells from IBD patients retain their suppressive activity. CD4+CD25high and FOXP3+ Treg cells are increased during remission but decreased during active disease. This contrasts with their strong increase in peripheral blood of patients with acute diverticulitis. Different than peripheral blood, inflamed IBD mucosa contains an increased number of CD4+CD25high T cells, FOXP3+ T cells, and transcripts for FOXP3 compared with noninflamed mucosa. However, the increase of FOXP3+ T cells in IBD lesions is significantly lower compared with inflammatory controls. Conclusions: The frequency of CD4+CD25+ Treg cells varies with IBD activity. Active IBD is not associated with a functional defect but with a contraction of the peripheral blood Treg pool and an only moderate expansion in intestinal lesions. Thus, compensatory mechanisms, numerically, are not successfully achieved in these diseases. [Copyright &y& Elsevier]

The human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) causes cell cycle arrest in G2. Vpr-expressing cells display the hallmarks of certain forms of DNA damage, specifically activation of the ataxia telangiectasia mutated and Rad3-related kinase, ATR. However, evidence that Vpr function is relevant in vivo or in the context of viral infection is still lacking. In the present study, we demonstrate that HIV-1 infection of primary, human CD4+ lymphocytes causes G2 arrest in a Vpr-dependent manner and that this response requires ATR, as shown by RNA interference. The event leading to ATR activation in CD4+ lymphocytes is the accumulation of replication protein A in nuclear foci, an indication that Vpr likely induces stalling of replication forks. Primary macrophages are refractory to ATR activation by Vpr, a finding that is consistent with the lack of detectable ATR, Rad17, and Chk1 protein expression in these nondividing cells. These observations begin to explain the remarkable resilience of macrophages to HIV-1-induced cytopathicity. To study the in vivo consequences of Vpr function, we isolated CD4+ lymphocytes from HIV-1-infected individuals and interrogated the cell cycle status of anti-p24Gag-immunoreactive cells. We report that infected cells in vivo display an aberrant cell cycle profile whereby a majority of cells have a 4N DNA content, consistent with the onset of G2 arrest. [ABSTRACT FROM AUTHOR]

Background & Aims: Regulatory CD25+ T cells (T(reg)) are effective in the prevention and down-regulation of inflammatory bowel disease (IBD) in animal models. Functional T(reg) cells are characterized by the expression of the transcription factor FOXP3 and show a CD4+ CD25(high) phenotype in humans. The aim of this study was to determine whether disease activity in IBD correlates with changes in frequency of T(reg) cells and their distribution in the intestinal mucosa., Methods: T(reg) cells were analyzed from peripheral blood and from biopsy specimens of IBD patients, inflammatory controls, and healthy volunteers by flow cytometry (CD4+ CD25(high)), immunochemistry (FOXP3), and real-time PCR (FOXP3). Regulatory properties of purified peripheral CD4+ CD25(high) T(reg) cells were determined by their suppressive effect on the proliferation of CD4+ CD25- T cells., Results: In peripheral blood, CD4+ CD25(high) T cells from IBD patients retain their suppressive activity. CD4+ CD25(high) and FOXP3+ T(reg) cells are increased during remission but decreased during active disease. This contrasts with their strong increase in peripheral blood of patients with acute diverticulitis. Different than peripheral blood, inflamed IBD mucosa contains an increased number of CD4+ CD25(high) T cells, FOXP3+ T cells, and transcripts for FOXP3 compared with noninflamed mucosa. However, the increase of FOXP3+ T cells in IBD lesions is significantly lower compared with inflammatory controls., Conclusions: The frequency of CD4+ CD25+ T(reg) cells varies with IBD activity. Active IBD is not associated with a functional defect but with a contraction of the peripheral blood T reg pool and an only moderate expansion in intestinal lesions. Thus, compensatory mechanisms, numerically, are not successfully achieved in these diseases.