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. 2008 Aug 15;378(1):48-57.
doi: 10.1016/j.virol.2008.05.018. Epub 2008 Jun 24.

Distinctive in vitro effects of T-cell growth cytokines on cytomegalovirus-stimulated T-cell responses of HIV-infected HAART recipients

Julie Patterson  1 , Renee Jesser, Adriana Weinberg
Affiliations

Distinctive in vitro effects of T-cell growth cytokines on cytomegalovirus-stimulated T-cell responses of HIV-infected HAART recipients

Julie Patterson et al. Virology. .

Abstract

Functional immune reconstitution is limited after HAART, maintaining the interest in adjunctive immune-modulators. We compared in vitro the effects of the gamma-chain T-cell growth cytokines IL-2, IL-4, IL-7 and IL-15 on cytomegalovirus-stimulated cell-mediated immunity. IL-2 and IL-15 increased cytomegalovirus-specific lymphocyte proliferation in HAART recipients, whereas IL-4 and IL-7 did not. The boosting effect of IL-2 and IL-15 on proliferation correlated with their ability to prevent late apoptosis. However, IL-2 increased the frequency of cells in early apoptosis, whereas IL-15 increased the frequency of fully viable cells. Both IL-2 and IL-15 increased cytomegalovirus-induced CD4+ and CD8+ T-cell proliferation and the synthesis of Th1 and pro-inflammatory cytokines and chemokines. However, only IL-2 increased the frequency of regulatory T cells and Th2 cytokine production, both of which have the potential to attenuate antiviral immune responses. Overall, compared to other gamma-chain cytokines, IL-15 had the most favorable profile for boosting antiviral cell-mediated immunity.

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Figures

Figure 1
Figure 1
Effect of T cell growth cytokines on CMV-specific proliferation and apoptosis of PBMC from HIV-infected and uninfected subjects. Data were derived from 36 HIV-infected subjects (median CD4=352 cells/µl; median plasma HIV RNA <400 copies/ml) and 18 healthy individuals. All PBMC cultures had a positive response to PWM defined by a ratio between PWM cpm/control antigen cpm ≥5. Bars represent means and SEM of untreated (white) and cytokine-treated (black) PBMC cultures. The effects of IL-2, IL-4, IL-7 and IL-15 are depicted in the first, second, third and fourth row, respectively. The first column shows proliferation (CMV cpm) calculated by subtracting the 3H-Thy incorporation of control antigen- from CMV-stimulated PBMC. The second column shows apoptosis, measured by the frequency of Annexin V+PI+ CMV-stimulated PBMC. The third column shows the association between the cytokine-induced increase in proliferation (delta log10CMV cpm, calculated by the difference between the log10CMV cpm in cytokine-treated and untreated PBMC cultures) vs. decrease in late apoptosis (delta % apoptosis, calculated by the difference between % Annexin V+PI+ CMV-stimulated PBMC in cytokine-untreated vs. treated cultures). The data in the third column were derived from 9 to 12 experiments using PBMC from HIV-infected subjects. p values were derived from paired T tests for comparisons of cytokine-treated with untreated cultures in the same group of subjects (continuous horizontal lines), unpaired T tests for comparisons of HIV-infected with uninfected subjects (interrupted lines); and linear regression for association analysis. All data passed normality distribution test.
Figure 2
Figure 2
CD4+ and CD8+ cell expansions in cultures stimulated with inactivated CMV antigen. The plots represent typical examples of CFSE-measured proliferation in HIV-infected (right 2 columns) and uninfected (left 2 columns) subjects. PBMC are labeled with CFSE prior to in vitro culture and uptake of CD4+ and CD8+ cells is verified after individually gating on each cell population (upper row). CFSE content is measured again after 6 days of in vitro stimulation with CMV (bottom row) and mock-infected control antigen (middle row). The plots show very few dividing cells (CFSElo) in mock-infected control-stimulated cultures, but a significant proportion of CD4+ and CD8+ cell divisions in CMV-stimulated PBMC.
Figure 3
Figure 3
Effect of IL-2 and IL-15 on CMV or control-antigen stimulated expansion of CD4+ and CD8+ PBMC from HIV-infected subjects on HAART. The bars represent means and SEM of results derived from 8 HAART recipients (median CD4= 322 cells/µl; median plasma HIV RNA< 400 copies/ml) of CMV-specific CFSElo T cell %. P values, calculated by paired T test, are noted above the horizontal lines that connect the bars representing the cell populations involved in the comparison.
Figure 4
Figure 4
Comparative effect of IL-2 and IL-15 on apoptosis of CMV-stimulated PBMC from HIV-infected subjects on HAART. Panel A shows a typical scatter plot. Live, early apoptotic and late apoptotic cells were measured by the % events in lower left, lower right and upper right quadrants, respectively. Total apoptosis was measured by the sum of % events in right lower and right upper quadrant. Data in panel B represent paired experiments of CMV-stimulated PBMC from 8 HIV-infected subjects (median CD4=322 cells/µl; median plasma HIV RNA<400 copies/ml) treated ex-vivo with IL-2 (light grey), IL-15 (dark grey), and no exogenous cytokines (white). Bars and lines represent means and SEM. Viable, early apoptotic and late apoptotic PBMC were defined as Annexin V−PI−, Annexin V+PI−, and Annexin V+PI+ cells, respectively. P values were derived by paired T test.
Figure 4
Figure 4
Comparative effect of IL-2 and IL-15 on apoptosis of CMV-stimulated PBMC from HIV-infected subjects on HAART. Panel A shows a typical scatter plot. Live, early apoptotic and late apoptotic cells were measured by the % events in lower left, lower right and upper right quadrants, respectively. Total apoptosis was measured by the sum of % events in right lower and right upper quadrant. Data in panel B represent paired experiments of CMV-stimulated PBMC from 8 HIV-infected subjects (median CD4=322 cells/µl; median plasma HIV RNA<400 copies/ml) treated ex-vivo with IL-2 (light grey), IL-15 (dark grey), and no exogenous cytokines (white). Bars and lines represent means and SEM. Viable, early apoptotic and late apoptotic PBMC were defined as Annexin V−PI−, Annexin V+PI−, and Annexin V+PI+ cells, respectively. P values were derived by paired T test.
Figure 5
Figure 5
Comparative effect of IL-2 and IL-15 on CD4+ and CD8+ Treg frequencies in PBMC from HIV-infected subjects on HAART. Panel A shows a typical scatter plot. Panel B presents the data from 8 subjects (median CD4=340 cells/µl; median plasma HIV RNA<400copies/ml). Lines connect results of the same donor.
Figure 5
Figure 5
Comparative effect of IL-2 and IL-15 on CD4+ and CD8+ Treg frequencies in PBMC from HIV-infected subjects on HAART. Panel A shows a typical scatter plot. Panel B presents the data from 8 subjects (median CD4=340 cells/µl; median plasma HIV RNA<400copies/ml). Lines connect results of the same donor.
Figure 6
Figure 6
Comparative effect of IL-2 and IL-15 on CMV-stimulated cytokine and chemokine production of PBMC from HIV-infected subjects on HAART. Bars represent means and SEM of cytokine or chemokine concentrations in CMV-stimulated PBMC culture supernatants after subtraction of concentrations in control antigen-stimulated PBMC from 22 HAART recipients (median CD4=315 cells/µl; median plasma HIV RNA <400 copies/ml). Asterisks indicate significant differences between cytokine-treated and untreated cultures (p<0.05 by paired T test).
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