ILT2Ig-Like Transcript 2
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If the immune checkpoint balance is in favor of negative signals, it will result in inhibition of T cell responses with exhausted T cells and cytotoxic T lymphocytes in anergy (APC: antigen-presenting cell; CTL: cytotoxic T lymphocyte; IL-10: interleukin-10; IL-35: interleukin-35; ILT2: immunoglobulin-like transcript-2; TCR: T cell receptor; TGF-[beta]: transforming growth factor-[beta]; Treg: regulatory T cell).
HLA-G binds to several immune cell inhibitory receptors, for example, ILT2, ILT3, and ILT4, to down-modulate immune responses of myelomonocytic cells, T cells, B cells, and NK cells.
In vitro experiments have shown (Figure 1) that HLAG/sHLA-G molecules derived from transplanted patients or from isolated cultured cytotrophoblast cells initiate a short-term inhibitory effect on T cells, NK cells, and B cells by binding with ILT2, ILT4, and KIR2DL4 [51-54].
An indirect inhibitory effect of HLA-G is that its presence leads to an enhanced expression of ILT2, ILT3, ILT4, and KIR2DL4 receptors in antigen-presenting cells, NK cells, and T cells.
In addition there is first evidence that myeloid cells are also sensitive to HLA-G, as they have ILT2 and ILT4 receptors expressed on cell surface.
Indeed, (i) HLA-G can downregulate the elimination phase by inhibiting the proliferation of T and B cells, the cytotoxic activity of NK cells and CTL, the phagocytic activity of neutrophils, and the function of DC, via ILT2 and ILT4 signaling [3,13-21] Figure 1).
In this regard, we recently demonstrated that proliferation of hematological tumors expressing HLA-G receptor (ILT2) maybe inhibited by HLA-G [ 37].
Because it was clearly demonstrated that HLA-G dimers carry most if not all of HLA-G immune-inhibitory functions [44-46], it is fair to state that currently, "tolerogenic HLA-G" is "dimeric B2M-associated HLA-G that acts through ILT2."
The human ligands for HLA-G are KIR2DL4 (CD158d) and immunoglobulin-like transcripts 2 and 4 (ILT2, ILT4).
The inhibitory NK receptors, KIR, ILT2, and CD94/NKG2A, poorly recognize porcine MHC-I molecule (SLA-I) including the pig ortholog for HLA-E leading to a lack of inhibitory signals (in dotted blue) and NK cell activation.