UL16-binding proteins (ULBP)

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UL16-binding proteins (ULBPs) may play important roles in mediating immune response to viruses and tumors, and the potential mechanism that UL16 may make human cytomegalovirus (HCMV) evade immune detection are currently being actively studied.

Introduction of ULBPs

ULBPs, also termed as retinoic acid early transcripts, encoded by RAET1 genes, a new family of MHC class I related molecules (MICs), were identified based on their ability to bind to HCMV glycoprotein UL16. ULBPs and MICs are ligands of natural killer (NK) cell receptor NKG2D/DAP10, which is an activated receptor expressed by NK cells and other immune effector cells.

ULBP gene family consists of 10 members, 6 of which encode potential functional glycoproteins, located at q24.2-q25.3 of the long arm tip, which is close to the human equivalent of mouse H2-linked t-complex. This subchromosomal region is similar to a segment of mouse chromosome 10, which contains a homologous MHC class I related retinoic acid early transcription loci, Raet1a-d. ULBP1, ULBP2, and ULBP3 are anchored to the membrane via glycosylphosphatidylinositol, while ULBP4 contains transmembrane and cytoplasmic domains.

The two genetic families of ligands for NKG2D. Fig.1 The two genetic families of ligands for NKG2D. (Fernández-Messina, 2012)

Function of ULBPs Recognition by γδ T Cells

Most human γδ T cells express the activated NKG2D, which plays an important role in the recognition and activation of γδ T cells. Studies have shown that NKG2D mediated immune recognition plays an important role in eliminating stressed cells, including tumors and virus-infected cells. As the ligand of NKG2D, ULBPs molecular ligands lead to the activation of cytotoxic effector lymphocytes in combination with NKG2D, and enhance the effector functions mediated by T cell receptors in the γδ T cell subset.

ULBPs in Cancer

Studies have shown that human γδ T cells recognize the stressful expression of ULBP4 molecules in tumor or pathogen-infected tissue cells through TCR and NKG2D, and are activated. They have strong cytotoxicity to tumors and EBV-infected B cells.

Specifically, immobilized soluble ULBP4 (rULBP4) has been shown to induce the proliferation of human ovarian epithelial cancer or colon cancer-derived Vδ2+ T cells in vitro. These Vδ2+ T cells secrete Th1 cytokines and show strong cytolytic activity on ULBP4 transfected target cells. In addition, it was also found that ULBP4 binds to the soluble chimeric protein containing TCR γ9/δ2 and activates TCR-Jurkat T cells transfected with TCRγ9/δ2.

Recent studies have found that ULBP4 is not only expressed on human tumor cells, but also peripheral blood cells infected with EBV. Because EBV infection can lead to lymphoma, it suggests that ULBP4 may be the target of γδ T cells to monitor B cell EBV infection and solid tumor spread in the bloodstream during tumor metastasis.

Tumor recognition by NK cells, cytokine-induced killer cells, and invariant NK T cells. Fig.2 Tumor recognition by NK cells, cytokine-induced killer cells, and invariant NK T cells. (Sabry, 2020)


  1. Fernández-Messina, L., et al. Human NKG2D-ligands: cell biology strategies to ensure immune recognition. Front Immunol. 2012.
  2. Sabry, M., Lowdell, M. W. Killers at the crossroads: The use of innate immune cells in adoptive cellular therapy of cancer. STEM CELLS Transl Med. 2020, 9: 974-984.
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