Regulatory T cells generated during cytomegalovirus in vitro stimulation of mononuclear cells from HIV-infected individuals on HAART correlate with decreased lymphocyte proliferation.
HIV-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 3H-thymidine incorporation; lower IFNgamma and TNFalpha production; higher CD4+ CD27- CD28- and CD8+ CD27- CD28- frequencies; lower CD4+ CD25hi; and higher FoxP3 expression in CD8+ CD25hi cells. CMV-specific proliferation correlated with higher IFNgamma, TNFalpha and IL10 levels and higher CD4+ perforin+ and CD8+ perforin+ frequencies. Decreased proliferation correlated with higher CD4+ CD27- CD28- frequencies and TGFbeta1 production, which also correlated with each other. Anti-TGFbeta1 neutralizing antibodies restored CMV-specific proliferation in a dose-dependent fashion. In HIV-infected subjects, decreased proliferation correlated with higher CMV-stimulated CD8+ CD25hi frequencies and their FoxP3 expression. These data indicate that FoxP3- and TGFbeta1-expressing regulatory T cells contribute to decreased immunity in HAART recipients.
Jesser
Renee D
RD
Department of Pediatric Infectious Diseases, University of Colorado Health Sciences Center, 4200 E. 9th Avenue, UCHSC School of Medicine, Denver, CO 80262, USA.
Li
Shaobing
S
Weinberg
Adriana
A
D000956:Antigens, Viral / Q000008:administration & dosage; D023241:Antiretroviral Therapy, Highly Active; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D003587:Cytomegalovirus / Q000276:immunology*; D004247:DNA / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007111:Immunity, Cellular; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D000956:Antigens, Viral; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D004247:DNA