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.
Se ha demostrado que algunos de estos receptores inhibidores son especificos para ciertas moleculas del CMH-I, asi: KIR2DL1 reconoce las moleculas HLA-Cw 2, 5 y 6; KIR2DL2 reconoce HLA-Cw 1, 3, 7 y 8; KIR2DL4 reconoce HLA-G; ILT2 reconoce HLA-G y el ILT 4 reconoce HLA-F.
(17) Caracteristicamente, ellos presentan una disminucion significativa en la frecuencia de las celulas NK [CD16.sup.low]/[CD56.sup.Hi] (subpoblacion inmunorreguladora) y una expansion de la subpoblacion de celulas [CD16.sup.Hi]/[CD56.sup.Low] (subpoblacion citotoxica); sin embargo, estas celulas NK anormalmente expandidas exhiben deficiente actividad citotoxica, baja produccion de citoquinas, aumento en la expresion de receptores inhibidores (KIR2DL2 e ILT2) y baja expresion de los NCR activadores (NKp30, NKp44 y NKp46).