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. 2013 Jun;93(6):943-50.
doi: 10.1189/jlb.1112580. Epub 2013 Mar 21.

CD8 down-regulation and functional impairment of SIV-specific cytotoxic T lymphocytes in lymphoid and mucosal tissues during SIV infection

Huanbin Xu  1 , Xiaolei Wang, Andrew A Lackner, Ronald S Veazey
Affiliations

CD8 down-regulation and functional impairment of SIV-specific cytotoxic T lymphocytes in lymphoid and mucosal tissues during SIV infection

Huanbin Xu et al. J Leukoc Biol. 2013 Jun.

Abstract

Functional impairment of virus-specific T cells is a hallmark of HIV/SIV infection, but the underlying mechanisms of this dysfunction are not well understood. To address this, we simultaneously analyzed the expression and intensity of CD8 and inhibitory PD-1 on CTL in blood and lymphoid tissues in SIV-infected rhesus macaques. The intensity (mean channel fluorescence) of CD8 expression was transiently down-regulated in early SIV infection (10-14 dpi), despite an increase in CD8(+) T cell proliferation. In chronic infection, CD8 expression was maintained at low levels on CD8(+) T cells in all tissues. Interestingly, Gag-specific CTLs were clearly divided into CD8high- and CD8low-expressing populations in SIV-infected macaques, and CD8low Gag-specific cells increased with disease progression, especially in lymphoid tissues when compared with peripheral blood or in Gag-vaccinated controls. Moreover, the CD8low CTL population secreted lower levels of cytokines upon SIV antigen stimulation and exhibited lower proliferative capacity during infection compared with the CD8high CTL population. Meanwhile, intensity of PD-1 expression on Gag-specific CTL in chronic infection was significantly higher than in acute SIV infection, although the frequencies of PD-1+ Gag-specific cells were similar in acute and chronic stages. In summary, down-regulation of CD8 expression and higher expression of PD-1 on SIV-specific CTLs could coordinately attenuate SIV-specific CTL responses and their ability to recognize virus-infected target cells, especially in lymphoid tissues, resulting in failure to contain viremia, and continued persistence and replication of HIV in lymphoid tissue reservoirs.

Keywords: CD8+ T cell; CTL; HIV; immunology; intestine.

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Figures

Figure 1.
Figure 1.. CD8 expression is down-regulated on total CD8+ T cells after SIV infection in peripheral and intestinal mucosal tissues.
(A) Absolute number of total CD8+ T cells in peripheral blood during SIV infection. (B) MFI of CD8 expression on CD8+ T cell in spleen, mesenteric (Mes) LN, jejunum (Jej), and colon lamina propria lymphocytes (LPL) post-SIV infection. (C) MFI of CD8 expression on circulating CD8+ T cells and activation state after SIV infection. (D) Proliferation (Ki67) of total CD8+ T cells in various tissues at different time-points post-SIV infection. *P < 0.05 compared with preinfection; #P < 0.05 compared with uninfected state for CD8+ T cell activation.
Figure 2.
Figure 2.. CD8 down-regulation on gag-CM9 populations, blood and lymphoid tissues, in vaccinated normal and chronically SIV-infected macaques, displaying two distinct populations: CD8high and CD8low Gag CM9+ cells.
(A and B) Representative FACS dot plots of CD8high and CD8low Gag CM9+ cells in various tissues in representative chronically SIV-infected (A) or SIV gag-vaccinated animals (B).
Figure 3.
Figure 3.. Dynamics of CD8high and CD8low Gag CM9+ cells in blood and lymphoid tissues at different time-points after SIV infection.
(A and D) Dynamics of total Gag-CM9 and Tat-SL8+ cells in various tissues in macaques after SIV infection. (B and D) Dynamics of CD8high Gag-CM9 or CD8high Tat-SL8+ cells in tissues post-SIV infection. (C and F) Dynamics of CD8low Gag-CM9 or CD8low Tat-SL8+ cells in tissues post-SIV infection. (G) Correlation of CD8low Gag-CM9+ cells in LNs with plasma viral load in chronically SIV-infected macaques. *P < 0.05 compared between 21 dpi or chronic infection and 14 dpi; **between 21 dpi and early chronic (D–F) or late chronic infection (C); #P < 0.05 compared between blood and other tissues.
Figure 4.
Figure 4.. Proliferation and cytokine responses of jejunum CD8high and CD8low CM9+ T cells in acute and chronically SIV-infected macaques.
(A) Representative flow cytometry dot plots showing distinct proliferation and cytokine secretion of CD8high and CD8low CM9+ cells in jejunum of SIV-infected animals in acute (HI63, 14 dpi) and late chronic infection (EA27). (B and C) Comparison of SIV-specific cytokine (TNF-α and IFN-γ) responses of CD8low and CD8high CM9+ cells in blood and jejunum between acute and late, chronic SIV infection in vitro. (D) Difference in proliferation of CD8low and CD8high CM9+ cells in blood and jejunum between acute and late chronic SIV infection in vivo. Acute: 14 dpi. *P < 0.05. Error bars represent sem.
Figure 5.
Figure 5.. PD-1 expression on Gag-CM9+ cells during acute and chronic SIV infection.
(A) Representative flow cytometry dot plots of PD-1 expression on CD8+CM9+ cells in blood and tissues in late, chronically SIV-infected macaques. (B) Percentage versus MFI of PD-1 expression on circulating CM9+ cells at different time-points post-SIV infection compared with vaccinated, uninfected animals. (C) Comparison of PD-1 intensity on CM9+ cells among vaccinated, acute (14, 21 dpi) and late chronically SIV-infected macaques in blood and mucosal tissues. *P < 0.05 compared with vaccinated (B) or acute infection (C). Error bars represent sd.
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