Regulatory T cells generated during cytomegalovirus in vitro stimulation of mononuclear cells from HIV-infected individuals on HAART correlate with decreased lymphocyte proliferation

摘要

HFV-infected patients fail to fully recover cell-mediated immunity despite HAART. To identify regulatory factors, we studied the phenotype and function of in vitro cytomegalovirus (CMV)-stimulated T cells from HAART recipients. CFSE-measured proliferation showed CD4(+) and CD8(+) cells dividing in CMV-stimulated cultures. Compared with healthy controls, CMV-stimulated lymphocytes from HAART recipients had lower 3 H-thymidine incorporation; lower IFN-gamma and TNF alpha production; higher CD4(+)CD27(-)CD28(-) and CD8(+)CD27(-)CD28(-) frequencies; lower CD4(+)CD25(hi); and higher FoxP3 expression in CD8(+)CD25(hi) cells. CMV-specific proliferation correlated with higher IFN-gamma, TNF alpha and IL10 levels and higher CD4(+)perforin(+) and CD8(+)perforin(+) frequencies. Decreased proliferation correlated with higher CD4+CD27-CD28- frequencies and TGF beta 1 production, which also correlated with each other. Anti-TGF beta 1 neutralizing antibodies restored CMV-specific proliferation in a dose-dependent fashion. In HIV-infected subjects, decreased proliferation correlated with higher CMV-stimulated CD8(+)CD25(hi) frequencies and their FoxP3 expression. These data indicate that FoxP3- and TGF beta 1-expressing regulatory T cells contribute to decreased immunity in HAART recipients. (c) 2006 Elsevier Inc. All rights reserved.