How MHC and Checkpoints Combat Cancer and Prevent Autoimmunity

Jeya Chelliah B.Vsc Ph.D.
The human immune system is an intricate network designed to protect us from a myriad of pathogens. At the heart of this system lie two critical components: Major Histocompatibility Complex (MHC) molecules and immune checkpoint proteins. Both play pivotal roles in immune regulation, but they operate through distinct mechanisms. Understanding how these components work together provides insights into preventing autoimmune diseases and developing innovative cancer treatments.

The Role and Function of MHC Molecules

MHC molecules are essential for the immune system’s ability to recognize foreign particles. These molecules present peptide fragments (antigens) derived from pathogens or the body’s own proteins on the surface of cells. This presentation is crucial for the immune system to distinguish between self and non-self.

• MHC Class I molecules are present on almost all nucleated cells and display peptides from inside the cell. If these peptides are abnormal or viral, they alert CD8+ T cells (cytotoxic T cells), which can then destroy the infected or malfunctioning cell.
• MHC Class II molecules are found on specialized antigen-presenting cells (APCs) like dendritic cells. They present antigens that have been engulfed and processed, signaling CD4+ T cells (helper T cells) to initiate a broader immune response, including B cell activation for antibody production.

The Role and Function of Immune Checkpoint Proteins

Immune checkpoint proteins act as regulators of the immune response, ensuring that it is appropriately activated and deactivated to prevent damage to healthy tissues. These molecules can be thought of as the immune system’s “brakes” and “accelerators,” fine-tuning the response to ensure it is proportional to the threat.

• CTLA-4 is an inhibitory receptor that dampens the early stages of T cell activation, preventing an overly aggressive immune response that could damage the body’s own cells.
• PD-1 is another inhibitory checkpoint that becomes relevant in the later stages of an immune response, particularly in peripheral tissues. It helps to wind down the immune response once the threat has been neutralized, further protecting the body from autoimmunity.

Why Both MHC Molecules and Immune Checkpoints Are Necessary

The dual mechanisms of MHC molecules and immune checkpoint proteins are essential for maintaining the delicate balance of the immune system. MHC molecules kickstart the immune response by identifying and presenting antigens, while immune checkpoints modulate this response, preventing it from becoming too aggressive and causing autoimmune diseases. This balance ensures that the body can defend itself against infections and other threats without harming its own tissues.

Overcoming Immune Checkpoints in Cancer Cells

Cancer cells often exploit immune checkpoints to avoid detection and destruction by the immune system. For instance, many tumors express high levels of PD-L1, which binds to PD-1 on T cells, effectively turning off the immune response against the tumor. Understanding the role of MHC molecules in antigen presentation has led to the realization that enhancing MHC presentation of tumor antigens can make tumors more visible to the immune system. Meanwhile, blocking immune checkpoints (using checkpoint inhibitors) can prevent tumors from hiding from the immune response, allowing T cells to attack the cancer more effectively.

The interplay between MHC molecules and immune checkpoint proteins is a testament to the complexity and sophistication of the immune system. While MHC molecules serve as the eyes of the immune system, identifying threats, immune checkpoints can be seen as the system’s judgment, determining the appropriate level of response. Together, they protect the body from both external and internal threats, maintaining a state of health and balance. Understanding these mechanisms not only sheds light on the prevention of autoimmune diseases but also paves the way for innovative cancer treatments that harness the body’s own defenses to fight the disease.