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. 2004 Aug;112(4):531-42.
doi: 10.1046/j.1365-2567.2004.01907.x.

Increased expression of the natural killer cell inhibitory receptor CD85j/ILT2 on antigen-specific effector CD8 T cells and its impact on CD8 T-cell function

M Nedim Ince  1 , Brooke Harnisch, Zhan Xu, Sang-Kyung Lee, Christoph Lange, Lorenzo Moretta, Michael Lederman, Judy Lieberman
Affiliations

Increased expression of the natural killer cell inhibitory receptor CD85j/ILT2 on antigen-specific effector CD8 T cells and its impact on CD8 T-cell function

M Nedim Ince et al. Immunology. 2004 Aug.

Abstract

We investigated whether inhibitory natural killer cell receptor (iNKR) expression contributes to impaired antigen-specific cytotoxicity and interferon-gamma (IFN-gamma) production by CD8 T cells during chronic infection. iNKR immunoglobulin-like transcript-2 (ILT2/CD85j) is expressed on 40-55% of cytomegalovirus (CMV)-, Epstein-Barr virus (EBV)- and human immunodeficiency virus (HIV)-specific CD8 T cells in both healthy and HIV-infected donors. Other iNKRs (CD158a, b1, e1/e2, k, CD94/NKG2A) are expressed on only a small minority of CD8 T cells and are not preferentially expressed on tetramer-staining virus-specific cells. In normal donors, ILT2 is expressed largely on perforin(+) CD27(-) effector cells. However, in HIV-infected donors, only a third of ILT2(+) cells are also perforin(+). In both normal and HIV-infected donors, ILT2(+) cells are prone to spontaneous apoptosis. Therefore, ILT2 is normally expressed during effector cytotoxic T-lymphocyte (CTL) differentiation, but can also be expressed when effector maturation is incomplete, as in HIV infection. The effect of ILT2 on CD8 cell function was assessed by preincubating effector cells with ILT2 antibody. While blocking ILT2 engagement has no appreciable effect on cytotoxicity, it increases antiviral IFN-gamma production by approximately threefold in both normal and HIV-infected donors. Thus, ILT2 expression, increased on antiviral CD8 cells in chronic infection, may interfere with protective CD8 T-cell function by suppressing IFN-gamma production.

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Figures

Figure 1
Figure 1
Immunoglobulin-like transcript-2 (CD85j/ILT2) is highly expressed on antigen-specific cells in healthy and human immunodeficiency virus (HIV)-seropositive individuals. Representative flow cytometry analysis is shown of inhibitory natural killer cell receptor (iNKR) expression on total and cytomegalovirus (CMV)-specific CD8 T cells in peripheral blood mononuclear cells (PBMCs) from (a) a healthy HIV-seronegative individual and (b) an asymptomatic HIV-seropositive donor. The first dot-plot for each sample displays the percentage of human leucocyte antigen (HLA)-A0201-CMV tetramer-positive cells in the lymphocyte gate. All the tetramer-positive cells are CD8high and form a well-separated population. Other dot-plots displaying NKR expression are gated on CD8high cells. The percentage of tetramer-positive and total CD8+ cells that stain above background for each iNKR are shown. The high proportion of CMV tetramer-positive cells in (a) that are CD94+ is not representative of the group of normal donor samples (Table 2).
Figure 2
Figure 2
Immunoglobulin-like transcript-2 (CD85j/ILT2) expression correlates with CD8 T-cell differentiation into effector cells. Representative flow cytometry analysis is shown of gated CD8high cells in peripheral blood mononuclear cells (PBMCs) from (a) an human immunodeficiency virus (HIV)-seronegative donor and (b) an HIV-seropositive donor. Cells were co-stained for ILT2 and CD27, CD45RA, or perforin. ILT2+ cells are preferentially CD27– and perforin-positive. For annexin V staining, cells co-stained for CD8, ILT2 and annexin V were analysed on gated subpopulations of ILT2+ or ILT2– CD8high cells. Spontaneous apoptosis was substantially higher amongst ILT2+ cells.
Figure 3
Figure 3
Immunoglobulin-like transcript-2 (CD85j/ILT2+) CD8 T cells are more often CD27– and perforin+ and have a higher rate of spontaneous apoptosis. Comparison of phenotypic properties of ILT2+ and ILT2– CD8 T cells in four healthy donors and four asymptomatic human immunodeficiency virus (HIV)-infected donors. The analysis was performed as described in the legend of Fig. 2.
Figure 4
Figure 4
Immunoglobulin-like transcript-2 (ILT2) and perforin expression change in parallel during the in vitro activation of CD8 T cells with anti-CD3. Peripheral blood mononuclear cells (PBMCs) from three normal donors were activated with a suboptimal concentration of anti-CD3 and analysed for expression of perforin and ILT2 on CD8+ lymphocytes on the indicated days. (a) Data from a representative donor; (b) and (c), the proportion of CD8 T cells staining for ILT2 and perforin, respectively, in all the samples.
Figure 5
Figure 5
Immunoglobulin-like transcript-2 (CD85j/ILT2) expression exerts little inhibitory effect on the cytotoxic function of CD8 T cells. (a) A human immunodeficiency virus (HIV) gag-specific CD8 T-cell clone showed, at most, a minimal inhibitory effect of ILT2 engagement on specific cytotoxicity. Cytotoxicity may be minimally enhanced in the presence of anti-ILT2 blocking antibody (◊) compared with isotype-control antibody (•), or no antibody (□), against gag peptide-armed targets. In the absence of peptide there is no killing (Δ). ILT2 blocking has no effect at all in specific lysis by three other antigen-specific T-cell lines (data not shown). (b) Blocking ILT2 also has no effect on specific lysis at limiting concentrations of peptide antigen. Effector cells, pretreated with blocking antibody (◊), control antibody (•), or no antibody (□), were tested for lysis of autologous B-LCLs treated with the indicated concentrations of cytomegalovirus (CMV) A0201-resticted peptide. (c) Freshly isolated peripheral blood mononuclear cells (PBMCs), stained for CMV A0201 peptide and selected for tetramer-positive CD8 T cells, were incubated with ILT2 or control antibody and used as effector cells. Blocking ILT2 increased the killing somewhat by one cell line, but not by another (data not shown). Preincunbation was performed in the presence of: (◊), blocking antibody; (•), control antibody; (□), no antibody.
Figure 6
Figure 6
Immunoglobulin-like transcript-2 (CD85j/ILT2) inhibits interferon-γ (IFN-γ) production by CD8 T cells. Non-adherent peripheral blood mononuclear cells (PBMCs) from one human immunodeficiency virus (HIV)-seropositive (a) and two HIV-seronegative (b–e) donors, preincubated with ILT2 blocking antibody, control antibody or no antibody, were mixed with Epstein–Barr virus (EBV) (b, c, e) or cytomegalovirus (CMV) (a, d) antigenic peptide-armed autologous adherent cells and analyzed for IFN-γ production. Percentages of CD8 T cells staining for intracellular IFN-γ are shown. The mean value ± standard deviation (SD) of the five experiments is also shown for each condition. The percentage of IFN-γ+ cells increases by approximately threefold when ILT2 engagement is blocked.
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