ABSTRACT
During human immunodeficiency virus (HIV) infection, phenotypic analysis of circulating gamma delta+ T cells showed a downregulation of the CD28 surface antigen, as recently demonstrated for CD4+ and CD8+ alpha beta+ T cells. The downregulation of the CD28 molecule predominated on CD8+ gamma delta+ T cells. Moreover, an increased expression of CD38 and/or HLA-DR molecules was found on gamma delta T cells as reported for alpha beta T cells indicating that all categories of circulating T lymphocytes share similar phenotypic abnormalities in HIV-infected patients. These unique changes in the different T-cell subsets might be induced by sustained activation of the immune system or by the rapid turnover of T cells and argue for a global dysregulation of T lymphocytes during HIV infection.
Subject(s)
Antigens, CD , Antigens, Differentiation, T-Lymphocyte/analysis , CD28 Antigens/analysis , HIV Infections/immunology , Receptors, Antigen, T-Cell, alpha-beta/analysis , Receptors, Antigen, T-Cell, gamma-delta/analysis , T-Lymphocyte Subsets/immunology , ADP-ribosyl Cyclase , ADP-ribosyl Cyclase 1 , Antigens, Differentiation/analysis , Female , Humans , Immunophenotyping , Male , Membrane Glycoproteins , N-Glycosyl Hydrolases/analysis , T-Lymphocyte Subsets/chemistryABSTRACT
Three-color automated flow cytometry was carried out on peripheral blood CD4+ and CD8+ T-lymphocytes of 42 HIV-positive patients using tri-color anti-CD4 or anti-CD8, phycoerythrin-anti-CD38, and fluorescein-anti-HLA-DR, mAbs to elucidate further the T-cell activation hypothesis recently proposed to explain CD4+ T-cell abnormalities observed during HIV infection. CD4+ CD38+ T-cells constituted the major part of circulating CD4+ T-cells in HIV-infected patients and their HLA-DR molecule positivity increased as their disease progressed. The level of CD38 and HLA-DR expression on CD4+ T-cells was positively correlated to that of CD8+ T-cells and to the level of beta 2-microglobulin. Next, to determine whether CD38 expression was associated with a selective expansion or deletion of V beta gene-defined subsets, we compared the V beta gene frequencies between CD38+ and CD38- T-cells from HIV-infected CDC stage II patients using 13 mAbs specific to V beta families. While selective expansion of certain V beta families was observed in CD4+ and CD8+ T-cells the T-cell receptor V beta subset distribution was similar among CD38+ and CD38-, CD4+ and CD8+ T-cells, suggesting that CD38+ expression was either independent of an HIV-encoded antigen-driven process or rather indicative of T-cell immaturity. It is proposed that the phenotype of circulating CD4+ and CD8+ T-cells of HIV-infected patients is a feature of two different mechanisms: (i) an in vitro activation state responsible for increased DR expression and selective expansion of V beta gene-defined subsets, and (ii) T-cell immaturity due to an increased turnover of these cells and accounting for increased CD38 expression.
Subject(s)
Acquired Immunodeficiency Syndrome/immunology , Antigens, CD , Antigens, Differentiation/metabolism , CD4-Positive T-Lymphocytes/immunology , HLA-DR Antigens/metabolism , N-Glycosyl Hydrolases/metabolism , Receptors, Antigen, T-Cell, alpha-beta/genetics , T-Lymphocyte Subsets/immunology , ADP-ribosyl Cyclase , ADP-ribosyl Cyclase 1 , Acquired Immunodeficiency Syndrome/pathology , Adult , Antiviral Agents/therapeutic use , CD4 Lymphocyte Count , CD4-CD8 Ratio , CD8-Positive T-Lymphocytes/immunology , Female , Gene Rearrangement, beta-Chain T-Cell Antigen Receptor , Humans , Lymphocyte Activation , Male , Membrane Glycoproteins , Middle Aged , Zidovudine/therapeutic use , beta 2-Microglobulin/metabolismABSTRACT
Since lymphoid organs constitute the site of active and progressive HIV disease, analysis of their lymphocytes may provide more accurate information on T cell abnormalities than that obtained from studying peripheral blood lymphocytes. The objective of this study was to compare the expressions of activation markers and T cell receptor (TCR) V beta gene products by CD4+ and CD8+ T cells in lymph nodes (LN) and peripheral blood (PB) from healthy individuals and asymptomatic HIV-infected patients to determine whether anomalies that could be identified at the HIV replication site could support the hypothesis of T cell activation by HIV-encoded antigens or superantigens. CD4+ and CD8+ T cells in paired LN and PB obtained from six healthy controls and five asymptomatic HIV-infected individuals were analysed by flow cytometry, using anti-CD38, anti-HLA-DR and 13 anti-V beta MoAbs that cover, approximately, 45% of the T cell repertoire. Analysis of T cell activation marker expression indicated that the percentages of CD4+ and CD8+ T cells bearing CD38 or CD38 and HLA-DR molecules were higher in patients than in controls and, in patients, higher in LN than in PB. Comparison between the V beta repertoires of CD4+ and CD8+ T cells in LN and PB showed that, in each healthy individual, a limited number of V beta families expressed by CD4+ or CD8+ T cells had different repartition in LN and PB, whereas in each HIV+ patient, more V beta families exhibited different distributions and these differences recurred among certain V beta segments, such as V beta 5.3 and V beta 21 in the CD4+ T cell population and V beta 5.2/5.3, V beta 12 and V beta 21 in the CD8+ T cell population. Taken together, these data argue for a skewed TCR repertoire in HIV infection and sustained activation of T cells by HIV-encoded antigens at the site of HIV replication, and further demonstrate that a high proportion of CD4+ T cells are in an activation state that may, indirectly, participate in their functional abnormalities.
Subject(s)
Antigens, CD/biosynthesis , HIV Infections/immunology , Lymphocyte Activation/immunology , Receptors, Antigen, T-Cell, alpha-beta/biosynthesis , T-Lymphocyte Subsets/immunology , Adult , Biomarkers/blood , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Gene Expression/immunology , Humans , Lymph Nodes/cytology , Male , Receptors, Antigen, T-Cell, alpha-beta/geneticsABSTRACT
In HIV infection, several arguments suggest a certain degree of CD4+ T cell activation which might contribute to lymphocyte dysfunctions. To investigate this possibility, we determined the phenotypes of circulating CD4+ T cells using monoclonal antibodies directed to activation markers and examined whether the defective in vitro interleukin-2 (IL-2) production by purified CD4+ T cells isolated from infected individuals was reversible in rested cultured T cells, a phenomenon suggestive of in vivo CD4+ T cell exhaustion. The number of CD4+ T cells expressing HLA-DR molecules was the same as that observed in controls, remained constant throughout the course of HIV infection, and constituted a major part of circulating CD4+ T cells. In CDC stage II group, the increased percentage of CD4+DR+ T cells was also associated with an increased expression of early activation markers. Defective IL-2 production in vitro was restored when CD4+ T cells were allowed to rest in culture. In addition, the number of circulating CD4+DR+ T cells correlated negatively with the in vitro IL-2 production induced by phytohemagglutinin and phorbol ester by freshly isolated CD4+ T cells. Taken together, these data suggest that in vivo activated CD4+ T cells may participate in the immune abnormalities of HIV infection.