Transforming growth factor-β-induced expression of CD94/NKG2A inhibitory receptors in human T lymphocytes

Abstract

Different HLA class I-specific killer inhibitory receptors (KIR) are expressed in vivo by a fraction of activated T cells, predominantly CD8+ , in which they may inhibit TCR-mediated cell functions. In an attempt to identify mechanisms leading to KIR expression in T cells, we analyzed the effect of transforming growth factor-g (TGF-g ) in T cells responding to bacterial superantigens in vitro. We show that TGF-g induces the expression of CD94/NKG2A in cells responding to toxic shock syndrome toxin 1 or to other staphylococcal superantigens. Remarkably, maximal CD94 expression occurred at (low) TGF-g concentrations which have no substantial effect on lymphocyte proliferation. Maximal CD94 expression occurred when TGF-g was added shortly after the cells were placed in culture. No expression could be induced in CD94/NKG2A-negative T cell clones. Although both CD4 + and CD8 + expressed CD94, the simultaneous expression of NKG2A was mostly confined to CD8 + cells. Monoclonal antibody-mediated cross-linking of CD94/NKG2A led to an impairment of T cell triggering via CD3, as determined in a redirected killing assay using the Fc + receptor-positive P815 murine target cells.

Activating CD94:NKG2C and inhibitory CD94:NKG2A receptors are expressed by distinct subsets of committed CD8+ TCR αβ lymphocytes

“…These conditions may, at least partially, be mimicked in vitro. It has been shown that CD8 + T cells express CD94 when stimulated in the presence of IL-15, TGF-b or IL-12 [21][22][23]. However, we found that the induction of CD94 in vitro merely reflects the potential of naive CD8 + T cells to up-regulate CD94 but that, in contrast to CD94:NKG2A + or CD94:NKG2C + T cells in vivo, this expression is transient.…”

“…Until to date, the presence of CD94 on memory-effector cells in variable stages of maturation [21][22][23] suggested somehow that CD8 + T cells could modulate CD94 expression during an immune response. Upregulation of CD94:NKG2A inhibitory receptors could then serve as a control of cells displaying too much autoreactivity [11].…”

“…Triggering of the TCR may induce CD94-expression, which is enhanced in the presence of IL-15, TGF-b or IL-12 [21][22][23]. Furthermore, intraepithelial T lymphocytes modulate CD94:NKG2A expression along with TCRengagement [9].…”

Expression of inhibitory KIR is confined to CD8+ effector T cells and limits their proliferative capacity

“…This has been achieved upon antigenic stimulation, both in vitro and in vivo [13,14]. In vitro, this phenomenon is potentiated by cytokines, such as IL-2, IL-10, IL-12, IL-15 and TGFb [15][16][17][18]. These observations are consistent with the in vivo expression of NKR on antigen-experienced T cells.…”

The NKG2 natural killer cell receptor family: comparative analysis of promoter sequences

“…20 Development of an NK-like phenotype, ie, de novo expression of CD94/NKG2-A can be induced by cytokines such as IL-2, IL-15 and TGF-␤ on immature thymocytes or Tc subsets. 21,22 NKG2 mRNA levels can be further increased by prolonged treatment of NK cells with IL-2 or IFN-␣, thus pointing to further regulation at the transcriptional level. 20,23 However, to date little is known about the promoter regions of NKG2 genes, which should harbor various regulatory elements mediating cell type-specific expression as well as cytokine responsiveness.…”