title: Differential susceptibility to activation-induced apoptosis among peripheral Th1 subsets: correlation with Bcl-2 expression and consequences for AIDS pathogenesis.
abstract: It has been proposed that HIV infection is associated with an imbalance in Th1 and Th2 subsets. Recent reports indicate that Th1 and Th2 effectors differ in their susceptibility to activation-induced apoptosis. To determine whether increased T cell apoptosis in HIV-infected patients contributes to alterations in cytokine synthesis, we performed single-cell analysis of type 1 and type 2 cytokine production by CD4 and CD8 T cells, simultaneously with detection of apoptosis. We demonstrate that a differential alteration in representation of Th1 subsets, rather than commitment of T cells to secrete Th2 cytokines, occurs throughout HIV infection. A significant decrease in the number of IL-2- or TNF-alpha-producing T cells was observed, whereas those producing IFN-gamma remained preserved. Furthermore, there is a gradient of susceptibility to activation-induced apoptosis (IL-2 < IFN-gamma < TNF-alpha) among the different Th1 subsets. This gradient was detected in both CD4 and CD8 subsets, as well as in control donors and HIV-infected patients, in whom the susceptibility to apoptosis of IL-2 and IFN-gamma producers was increased compared with controls. This differential intrinsic apoptosis susceptibility of Th1 effectors was found to be tightly regulated by Bcl-2 expression. In HIV-infected persons, disappearance of IL-2-producing T cells was a good indicator of disease progression and was correlated with the progressive shrinkage of the CD4+ CD45RA+ T cell compartment and a gradual increased susceptibility to activation-induced apoptosis of the IL-2-producing subset. This close relationship between the CD45RA/CD45R0 ratio, the level of type 1 cytokine production, and susceptibility to apoptosis should be considered in HIV-infected patients under antiviral or immune-based therapies.
authors.affiliation: Département SIDA et Rétrovirus, Institut Pasteur, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Ledru
authors.forename: H
authors.initials: H
authors.lastname: Lecoeur
authors.forename: S
authors.initials: S
authors.lastname: Garcia
authors.forename: T
authors.initials: T
authors.lastname: Debord
authors.forename: M L
authors.initials: ML
authors.lastname: Gougeon
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000209:etiology / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000145:classification; D018450:Disease Progression; D004198:Disease Susceptibility; D015658:HIV Infections / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D007399:Interphase / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000032:analysis; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D018417:Th1 Cells / Q000145:classification / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D007376:Interleukin-2; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1