Week 3: T Cell Receptors and Invariant Natural Killer T Cells

Hello! My name is Sidharth, and this week I’ll discuss the role of T cell receptors (TCRs) in the immune system and in “off-the-shelf” CAR T-cells.

What are T cell receptors?

T cell receptors (TCRs) are protein complexes that are found on the surface of T cells. They recognize antigens (proteins from pathogens) that are bound to HLA molecules*. These receptors are crucial to our bodies’ defense system because they can also detect enemy HLA complexes. Unfortunately, this poses a major problem when it comes to engineering “off-the-shelf” CAR T-cells.

*For more information on MHC/HLA complexes, please see my blog on Human Leukocyte Antigens.

Pictured: T Cell Receptor Binding to an Antigen Presenting Cell Credit: Sun et al., 2021

TCRs and “Off-the-Shelf” CAR T-cells

“Off-the-shelf” CAR T-cells are forged using cells from donors. Every individual has a unique TCR that accepts their own HLA complexes and rejects foreign HLA complexes. Therefore, “off-the-shelf” CAR T cells will recognize a patient’s immune cells as foreign, creating full-fledged immune warfare, also known as Graft v. Host disease. What’s the solution? It’s simple, delete the gene that codes for the TCR. And scientists have already shown that this could be done. (Depil et al., 2020)

Thus far, I’ve illustrated two sources of immune rejection: the non-matching of HLA genes and the presence of the TCR receptor on “Off-the-shelf” CAR T-cells. Discovery: In order to create viable “Off-the-shelf” CAR T-cells, the engineered cells must be HLA-matched (as close as possible) and have a deleted TCR. Most research articles I’ve read discuss one method or the other, but ensuring that both processes are complete will help to reduce immune rejection greatly.

Even if all the precautions are taken, immune rejection can occur. But it’s much more unlikely. Why? Our immune system has other defense mechanisms such as minor histocompatibility complexes (not to be confused with major histocompatibility complexes) that can protect us against invading cells.

Invariant Natural Killer T Cells (iNKT Cells)

Every individual contains a small portion of invariant natural killer T cells that are common among all people. These iNKT cells have a TCR that is also common, making them a great candidate for “Off-the-shelf” cell therapies. Preliminary studies have also shown that blood stem cell derived iNKT cells could be effective in treating cancer. (Zhu et al., 2019, Wolf et al., 2018) As I continue with my research, I’ll keep a close eye on iNKT cells and explore how they could be used to create cancer immunotherapies.

Conclusion

This week, I explored TCRs and their role in immune rejection. TCRs must be deleted from “Off-the-shelf” CAR T-cells to avoid Graft v. Host disease. I discovered that there are also other alternatives to T cells, such as iNKT cells, that may be able to trick parts of our immune defense system. Be sure to tune in next week as I attempt to unravel more secrets of our profound immune system.

Sidharth