Immune Activation and CD8(+) T-Cell Differentiation towards Senescence in HIV-1 Infection

Progress in the fight against the HIV/AIDS epidemic is hindered by our failure to elucidate the precise reasons for the onset of immunodeficiency in HIV-1 infection. Increasing evidence suggests that elevated immune activation is associated with poor outcome in HIV-1 pathogenesis. However, the basis of this association remains unclear. Through ex vivo analysis of virus-specific CD8(+) T-cells and the use of an in vitro model of naïve CD8(+) T-cell priming, we show that the activation level and the differentiation state of T-cells are closely related. Acute HIV-1 infection induces massive activation of CD8(+) T-cells, affecting many cell populations, not only those specific for HIV-1, which results in further differentiation of these cells. HIV disease progression correlates with increased proportions of highly differentiated CD8(+) T-cells, which exhibit characteristics of replicative senescence and probably indicate a decline in T-cell competence of the infected person. The differentiation of CD8(+) and CD4(+) T-cells towards a state of replicative senescence is a natural process. It can be driven by excessive levels of immune stimulation. This may be part of the mechanism through which HIV-1-mediated immune activation exhausts the capacity of the immune system

Antigen Potency and Maximal Efficacy Reveal a Mechanism of Efficient T Antigen Potency and Maximal Efficacy Reveal a Mechanism of Efficient T Cell Activation

The following resources related to this article are available online at http://stke.sciencemag.org. Article Tools http://stke.sciencemag.org/cgi/content/full/sigtrans;4/176/ra39 Visit the online version of this article to access the personalization and article tools: T cell activation, a critical event in adaptive immune responses, depends on productive interactions between T cell receptors (TCRs) and antigens presented as peptide-bound major histocompatibility complexes (pMHCs). Activated T cells lyse infected cells, secrete cytokines, and perform other effector functions with various efficiencies, which depend on the binding parameters of the TCR-pMHC complex. The mechanism through which binding parameters are translated to the efficiency of T cell activation, however, remains controversial. The "affinity model" suggests that the dissociation constant (K D ) of the TCR-pMHC complex determines the response, whereas the "productive hit rate model" suggests that the off-rate (k off ) is critical. Here, we used mathematical modeling to show that antigen potency, as determined by the EC 50 (half-maximal effective concentration), which is used to support K D -based models, could not discriminate between the affinity and the productive hit rate models. Both models predicted a correlation between EC 50 and K D , but only the productive hit rate model predicted a correlation between maximal efficacy (E max ), the maximal T cell response induced by pMHC, and k off . We confirmed the predictions made by the productive hit rate model in experiments with cytotoxic T cell clones and a panel of pMHC variants. Thus, we propose that the activity of an antigen is determined by both its potency (EC 50 ) and maximal efficacy (E max ). Material

M1-like monocytes are a major immunological determinant of severity in previously healthy adults with life-threatening influenza

In each influenza season, a distinct group of young, otherwise healthy individuals with no risk factors succumbs to life-threatening infection. To better understand the cause for this, we analyzed a broad range of immune responses in blood from a unique cohort of patients, comprising previously healthy individuals hospitalized with and without respiratory failure during one influenza season, and infected with one specific influenza A strain. This analysis was compared with similarly hospitalized influenza patients with known risk factors (total of n = 60 patients recruited). We found a sustained increase in a specific subset of proinflammatory monocytes, with high TNF-α expression and an M1-like phenotype (independent of viral titers), in these previously healthy patients with severe disease. The relationship between M1-like monocytes and immunopathology was strengthened using murine models of influenza, in which severe infection generated using different models (including the high-pathogenicity H5N1 strain) was also accompanied by high levels of circulating M1-like monocytes. Additionally, a raised M1/M2 macrophage ratio in the lungs was observed. These studies identify a specific subtype of monocytes as a modifiable immunological determinant of disease severity in this subgroup of severely ill, previously healthy patients, offering potential novel therapeutic avenues

Invariant NKT cells reduce the immunosuppressive activity of influenza A virus-induced myeloid-derived suppressor cells in mice and humans.

Infection with influenza A virus (IAV) presents a substantial threat to public health worldwide, with young, elderly, and immunodeficient individuals being particularly susceptible. Inflammatory responses play an important role in the fatal outcome of IAV infection, but the mechanism remains unclear. We demonstrate here that the absence of invariant NKT (iNKT) cells in mice during IAV infection resulted in the expansion of myeloid-derived suppressor cells (MDSCs), which suppressed IAV-specific immune responses through the expression of both arginase and NOS, resulting in high IAV titer and increased mortality. Adoptive transfer of iNKT cells abolished the suppressive activity of MDSCs, restored IAV-specific immune responses, reduced IAV titer, and increased survival rate. The crosstalk between iNKT and MDSCs was CD1d- and CD40-dependent. Furthermore, IAV infection and exposure to TLR agonists relieved the suppressive activity of MDSCs. Finally, we extended these results to humans by demonstrating the presence of myeloid cells with suppressive activity in the PBLs of individuals infected with IAV and showed that their suppressive activity is substantially reduced by iNKT cell activation. These findings identify what we believe to be a novel immunomodulatory role of iNKT cells, which we suggest could be harnessed to abolish the immunosuppressive activity of MDSCs during IAV infection

CD8⁺ T-Cell Differentiation and Senescence

<div><p>(A) Expression of the replicative senescence-associated marker CD57 on antigen-experienced CD8⁺ T-cell subsets. The percentage and mean fluorescence intensity for the CD57⁺ cells are shown for one single donor. Data on several donors (HIV-1-infected or healthy) are also shown (<i>n</i> = 24).</p> <p>(B) Expression of CD57 on CD8⁺ T-cells (whole population or antigen-specific) from acute to postacute (on ART) HIV-1 infection.</p> <p>(C) CD69 expression and CFSE proliferation profile for CD8⁺ T-cell subsets gated on the basis of CD57 and CD27 expression following stimulation with anti-CD3 antibodies. PBMCs were analysed for CD69 expression after 18 h and CFSE labeling after 6 d. Percentages of proliferating cells (with background subtracted) are indicated. Representative results from three experiments (one HIV-infected and two healthy donors) are shown.</p> <p>(D) Telomere length measurement by flow FISH on naïve and antigen-experienced CD8⁺ T-cell subsets FACS-sorted on the basis of CD57, CD27, CCR7, and CD45RA expression. The average length of telomeres was obtained by substracting the mean fluorescence of the background control (no probe; open histogram) from the mean fluorescence obtained from cells hybridised with the FITC-labeled telomere probe (gray histogram). Representative results from two experiments (on healthy donors) are shown.</p> <p>(E) CD57 and perforin expression in the CD8⁺ T-cell population dissected into naïve (CD27^+high, perforin-negative), antigen-experienced CD27⁺ (perforin^low), and antigen-experienced CD27⁻ perforin^low or perforin^high subsets. The percentage and mean fluorescence intensity for the CD57⁺ cells are indicated.</p> <p>(F) Representative staining for perforin and CD57 in CD8⁺ T-cells from a HIV-1-infected or a healthy donor. Percentages of cells present in the top quadrants are shown.</p> <p>(G) Representative staining for perforin and CD57 in CD4⁺ T-cells from an HIV-1-infected or a healthy donor. Percentages of cells present in the top quadrants are shown.</p></div

CD8⁺ T-Cell Differentiation and HIV-1 Disease Progression

<div><p>(A) Distribution of the CD8⁺ T-cell population in differentiated subsets (CD28⁺/CD27⁺ early, CD28⁻/CD27⁺ intermediate, and CD28⁻/CD27⁻ late) through the course of HIV-1 infection. Abbreviations: H, healthy (<i>n</i> = 15); A, acute HIV infection (<i>n</i> = 11); C, chronic HIV infection nonprogressor (no ART; <i>n</i> = 14); P, chronic HIV infection with signs of disease progression (no ART; <i>n</i> = 10). Statistics: * <i>p</i> < 0.0001 with the ANOVA test and <i>p</i> < 0.005 between each group.</p> <p>(B) Percentages of CD27⁻ CD8⁺ T-cells that are specific for HLA-B8 HIV (nef) or HLA-A2 CMV in HIV-1-infected individuals at different stages of infection. Statistics: ** <i>p</i> < 0.005 with the nonparametric Mann–Whitney test.</p> <p>(C) Inverse correlation between CD4⁺ T-cell counts and percentage of highly differentiated CD27⁻ cells in the whole CD8⁺ T-cell population of HIV-1-infected donors during chronic infection (untreated nonprogressors and progressors). The <i>p</i> value was obtained using the nonparametric Spearman rank correlation test.</p></div

CD8⁺ T-Cell Activation during Acute HIV-1 Infection

<div><p>(A) Percentages of activated CD38⁺ cells (gated on whole CD8⁺ T-cells, HIV tetramer-positive CD8⁺ T-cells, or whole CD4⁺ T-cells) in donors during acute HIV-1 infection and later postacute on ART (<i>n</i> = 12); healthy donors (<i>n</i> = 11) and untreated donors with nonprogressing chronic infection (<i>n</i> = 12) are also shown.</p> <p>(B and C) CD38 and Ki67 expression on CD8⁺ T-cell subsets defined by CD45RA/CD62L (B) or CD28/CD27 (C) expression, shown in one single donor from acute to postacute (on ART) HIV-1 infection. Percentages of positive cells are shown. Means (± SEM) of CD38⁺ and Ki67⁺ CD8⁺ T-cells for ten patients are also shown; statistics concern CD38 expression.</p> <p>(D) Staining for the activation marker CD38 on CMV-, EBV-, or influenza A virus-specific CD8⁺ T-cells during acute and postacute (on ART) HIV-1 infection in a single donor. Percentages of CD38⁺ tetramer-positive CD8⁺ T-cells are shown. Data on all donors (see <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0020020#pbio-0020020-t001" target="_blank">Table 1</a>) are also shown.</p> <p>(E) Activation (CD38 and Ki67 staining) of CMV-specific CD8⁺ T-cells or whole CD8⁺ T-cell population during acute and postacute (on ART) HIV-1 infection in a single donor. Percentages of cells present in quadrants are shown.</p> <p>Statistics: * <i>p</i> < 0.002, ** <i>p</i> < 0.01, NS = nonsignificant, with the nonparametric Mann–Whitney test.</p></div