ILT-4

ILT-4 (immunoglobulin-like transcript 4, LILRB2, CD85d) is an inhibitory leukocyte immunoglobulin-like receptor expressed on myeloid antigen-presenting cells-monocytes, macrophages, dendritic cells and neutrophils-and on endothelial cells. ILT-4 is a type I transmembrane protein with four extracellular Ig domains that bind a broad spectrum of HLA class I molecules including HLA-A, HLA-B, HLA-C (weakly), HLA-F and, notably, HLA-G with high affinity; its cytoplasmic tail contains four ITIM motifs that recruit SHP-1/SHP-2 to dampen Fc receptor, TLR and cytokine receptor signaling. Through HLA-G engagement at the maternal-fetal interface and in transplanted tissues, ILT-4 induces tolerogenic dendritic cells, suppresses T-cell priming and expands regulatory T cells. In cancer, ILT-4 on tumor-associated macrophages and dendritic cells mediates immunosuppression; tumor-cell expression of HLA-G engages ILT-4 to impair NK and T-cell function, and high ILT-4 expression correlates with poor prognosis. ILT-4 blockade is therefore being developed to reinvigorate antitumor immunity and to modulate transplantation and autoimmune inflammation.