Gee whiz: HLA-G in placental development and pancreatic islet transplantation

Gee whiz: HLA-G in placental development and pancreatic islet transplantation

By: Shruthi Kandalai

Islet cell transplantation, or transplanting insulin-producing islet cells from donors into patients, has been proposed as a method to treat T1D without daily insulin injections. However, it remains that immune recognition of transplanted cells as foriegn can limit the activity of transplants. As a result, many patients that undergo transplants are required to take immunosuppressive drugs to prevent transplant cell rejection, which tend to have significant side effects. Helping patients achieve immune tolerance of the grafts may allow transplants to function, without side effects of immunosuppressive drugs. One of the most well-known conditions of immune tolerance relates to pregnancy, where a mother’s immune system tolerates the embryo, while still continuing to fight off other foreign invaders. Understanding how the immune system achieves immune tolerance during pregnancy may shed light on future efforts to create a similar immune tolerance of islet transplants in patients.

Multiple papers have explored HLA-G as a regulator for placental cells to avoid immune attack. HLA-G is expressed on extravillous trophoblasts (EVTs) that line the placenta. EVTs help educate maternal leukocytes and other immune cells and can also contribute to placental vascular and tissue remodeling. 

  • A study found that HLA-G regulates early interactions of trophoblasts and may play a role in immune avoidance. HLA-G typically regulates innate and adaptive immune responses and promotes tolerance of placenta and tissue remodeling.
    • Interactions of HLA-G lead macrophages, effector and regulatory T cells and B cells to infiltrate the uterine lining, helping create placental tolerance.
    • Interactions between dendritic cells and HLA-G may reprogram immune tolerance.
    • HLA-G may interact with heat shock proteins, which activate NK cells and regulatory T cells.
  • A recent study further explored three types of trophoblasts that may play a role in immune regulation.
    • HLA-G EVTs induce regulatory T cells highly in the first trimester, when immune tolerance still needs to be developed. Induction decreases across the pregnancy, with the levels lower by term.
    • EVT types studied (HLA-C, HLA-E and HLA-G) varied across pregnancy, with HLA-C and HLA-E highest during the first trimester. All three can induce regulatory T cells, but further research is needed for the mechanisms.
  • A 2006 paper proposed that HLA-G expression may also be used as an immunomodulatory molecule for pancreatic islet transplants.
    • Transgenic expression of viral antigens in islets does not elicit an immune response, so shielding islet transplants is possible.
    • Expression of HLA-G has been detected in insulin and glucagon positive cells, showing that this expression is present in endocrine regions of the pancreas.
    • HLA-G antigens increase when islets are plated with cytokines.
    • HLA-G and MHC work together to prevent lysis from NK cells.
    • Islet cells cultured with high glucose and insulin secretagogues increase surface expression of HLA-G, indicating that glucose stimulation may regulate HLA-G.

The takeaway: Avoiding immune cell attack is important for islet cell transplantation, and better understanding how fetuses do so during pregnancy through HLA-G may help to better inform future directions. HLA-G may be normally expressed and could be inducibly upregulated in transplanted cells to prevent immune detection and thus, should be explored further regarding islet transplants.


  • Gregori, S., Amodio, G., Quattrone, F., & Panina-Bordignon, P. (2015). HLA-G Orchestrates the Early Interaction of Human Trophoblasts with the Maternal Niche. Frontiers in Immunology, 6(128).
  • Papuchova, H., Kshirsagar, S., Xu, L., Gomes, H. A., Li, Q., Iyer, V., . . . Tilburgs, T. (2020). Three types of HLA-G+ extravillous trophoblasts that have distinct immune regulatory properties. Proceedings of the National Academy of Sciences, 117(27), 15772-15777.
  • Zalatan, J., Mcmaster, M., Prinsen, R., Salomon, D. R., Ricordi, C., Torbett, B. E., . . . Crisa, L. (2006). The Class I HLA Repertoire of Pancreatic Islets Comprises the Nonclassical Class Ib Antigen HLA-G. Diabetes, 55(5), 1214-1222.

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