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. 2012 Jun;26(6):2294-305.
doi: 10.1096/fj.11-195180. Epub 2012 Feb 28.

Rapid down-regulation of γc on T cells in early SIV infection correlates with impairment of T-cell function

Huanbin Xu  1 , Xiaolei Wang, Bapi Pahar, Xavier Alvarez, Kelsi K Rasmussen, Andrew A Lackner, Ronald S Veazey
Affiliations

Rapid down-regulation of γc on T cells in early SIV infection correlates with impairment of T-cell function

Huanbin Xu et al. FASEB J. 2012 Jun.

Abstract

The common γ(c) subunit molecule is shared among all γ(c) cytokines and clearly involved in T-cell function, but its role in HIV infection and immunity is not well understood. Here, we examined expression and function of γ(c) on T cells during SIV infection in Rhesus macaques. Surface γ(c) distribution was differentially expressed on CD4(+) and CD8(+) T cells, and CD4(+) naive/memory cell populations in various lymphoid tissues of normal macaques. However, surface γ(c) expression was rapidly and significantly down-regulated on T cells in acute infection with pathogenic SIV, compared to infection with a less virulent SHIV or controls and did not recover on CD8(+) T cells in the chronic stage. Moreover, the peripheral and CD4(+)T cell loss was inversely correlated with γ(c)(+) CD8(+) T cells in individual tissues. γ(c)(+) T cells were mainly functional as evidenced by higher cytokine secretion and proliferative capacity. Further in vitro experiments found that surface γ(c) expression could be down-regulated following high level of IL-7 treatment by both internalization and shedding. Down-regulation of γ(c) during early HIV/SIV infection may inhibit T-cell function, particularly of CD8(+) T cells, and, may be linked with immune failure and loss of viral containment.

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Figures

Figure 1.
Figure 1.
Surface expression of γc on T cells in various tissues of normal macaques. A) Representative dot plots showing the gating strategy for identifying γc+ CD3+ T lymphocytes and distribution of γc+ CD4+/CD8+ T-cell subsets, defined here as naïve, CD45RA+CCR7+; effector memory, CD45RA+/CD45RA−CCR7−; and central memory, CD45RA−CCR7+, in different tissues. Mes Ln, mesenteric lymph node; Jej LPL, jejunum lamina propria lymphocyte. B) Frequency of γc+ CD4+ (open bars) or γc+CD8+ (solid bars) as a percentage of gated CD3+ T cells in peripheral blood and various lymphoid tissues from normal Rhesus macaques. C) Group data showing the mean frequency of naive (CD45RA+CCR7+), central memory (Tcm; CD45RA-CCR7+), and effector memory (Tem; CD45RA+/CD45RA−CCR7−) gated γc+ CD4/CD8+ T cells in blood, mesenteric lymph node (LN), jejunum lamina propria lymphocyte (LPL), and vagina (n=7 for each tissue). Error bars represent means ± se. *P < 0.05 vs. peripheral blood.
Figure 2.
Figure 2.
Marked down-regulation of surface γc expression occurs on circulating and mucosal T cells in acute SIV infection of macaques. A, B) Note γc expression on blood CD4+ T cells (A) or CD8+ T cells (B) during SIV infection. Dpi, days postinfection. C, D) Comparison of γc expression on circulating CD4+ (C) or CD8+ (D) T cells between macaques infected with pathogenic SIVmac251 (n=10) or the less pathogenic SHIV162p3 (n=11). E, F) Note γc expression on CD4+ (open bars) or CD8+ (solid bars) T cells in mesenteric lymph node (E) and lamina propria lymphocytes from the jejunum (F) in naive (n=5), acute (n=7), and chronically SIVmac251-infected animals (n=8). G, H) Correlation between CD4+ T-cell loss and γc expression on CD8+ T cells in the peripheral blood (G) or jejunum lamina propia lymphocytes (LPL; H) in naive and SIV-infected macaques. I, J) Correlation of γc expression on CD4+ (I) or CD8+ T cells (J) with viral loads in plasma during SIV infection (n=41). Error bars represent means ± se. *P < 0.05, **P < 0.01, ***P < 0.001 vs. normal group. #P < 0.05 vs. SIVmac251 group.
Figure 3.
Figure 3.
Proliferation (Ki-67+) of γc+ T cells during SIV infection. A) Representative dot plots showing Ki-67 levels on γc+/γc− CD3+ T cells. B, C) Proliferation of γc+ CD4+ or CD8+ T cells compared with γc populations during SIVmac251 infection in macaques (n=21). C, D) Correlation of proliferating (Ki-67+) γc+ T cells with γc levels on CD4+ (D) and CD8+ (E) T cells in the naive and SIV-infected macaques. Error bars represent means ± se. *P < 0.01 vs. γc+ population.
Figure 4.
Figure 4.
Surface γc expression on functional (cytokine-secreting) SIV-specific CD4+ or CD8+ T cell subsets. A) No significant differences in γc expression on CD4+ or CD8+ T cells were detected between naive (solid bars; n=4) and spontaneous controllers (open bars; n=4) animals. B, C) Note that most SIV-specific CD4+ (B) and CD8+ (C) T cells derived from spontaneous controllers that are producing cytokines in response to SIV peptides coexpress γc+ as compared to the γc− cells. Experimental samples (Exp) represent SIV peptide stimulation. PBMCs were derived from naive (uninfected) or chronically SIV-infected animals that eventually controlled infection to undetectable levels (n=4). D, E) γc+ CD4+ or γc+ CD8+ T cells from naive animals have higher proliferative capacity after treatment with γc receptor-sharing cytokines, including IL-2 (20 U/ml), IL-7 (20 ng/ml), and IL-15 (20 ng/ml) or combination for 24 h in vitro. F) Phosphorylated STAT5 levels in the γc+/γc− T cells from naive animals after combined treatment with IL-2, IL-7, and IL-15 cytokines for 30 min. Data represent means ± sd of ≥3 independent experiments.
Figure 5.
Figure 5.
Surface and intracellular γc coexist in T cells from normal animals. Confocal microscopy performed on live cells (A) and permeabilized cells (B) confirmed both surface γc (A) or intracellular and surface γc expression (red; B) on CD3+ T cells (green). Images at left of each confocal image are the individual channels shown in the merged image at right. Green, CD3; red, CD132 (γc); blue, ToPro-3 (nuclear stain).
Figure 6.
Figure 6.
γc cytokine levels in plasma in SIV-infected macaques and effects of SIV infection on γc expression on T cells in vitro. A) Dynamics of γc cytokine (IL-2, IL-7, and IL-15) levels in plasma of SHIV162p3- or SIV-infected macaques. These γc cytokines were detected in plasma by cytokine bead array at different time points postinfection in 9 SIVmac251-infected and 6 SHIV162p3-infected macaques. B) Correlation of γc cytokine levels with viral loads in plasma in SIVmac251-infected macaques. C) γc expression on CD4+ or CD8+ T cells after SIVmac251 infection in vitro (n=8). Error bars represent means ± se. *P < 0.05 between SHIV162p3- or SIV-infected macaques.
Figure 7.
Figure 7.
Membrane γc regulation after IL-2, IL-7, and IL-15 treatment in vitro. A, B) Regulation of surface γc expression on CD4+ (A) or CD8+ (B) T cells by IL-2, IL-7, IL-15 alone or combination treatments, as indicated on the x axis. C) Representative FACS histogram of surface γc expression on CD4+ or CD8+ T cells after IL-7 (20 ng/ml) treatment for 30 min in vitro. Black histogram, antibody isotype control; blue histogram, surface γc; purple histogram, total γc; red histogram, surface staining and then IL-7 treatment; green histogram, IL-7 treatment followed by surface staining. D) γc surface and intracellular γc expression on CD4+ T cells after IL-7 (solid bars) or IL-15 alone (striped bars) treatment for 30 min. E) γc surface and intracellular γc expression on CD8+ T cells after IL-7 (solid bars) or IL-15 alone (striped bars) treatment for 30 min. Note that IL-7 promotes both extracellular γc shedding and internalization on T cells. F–H) Surface γc CD4+ (F) or CD8+ (G) expression on T cells was down-regulated in a dose-dependent manner after 24 h or over 7 d (H) treatment with IL-7 in vitro. PBMCs were treated by IL-7 or IL-15 alone at 20 ng/ml. Error bars represent means ± sd. Data are representative of ≥3 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001.
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