Mutual Regulation of Immune Checkpoints

The intricacies of immune checkpoint regulation extend far beyond their individual functions. Recent breakthroughs have illuminated the phenomenon of mutual regulation, a concept that reveals the dynamic interplay between these checkpoints. CTLA-4, for instance, not only fine-tunes T-cell activation but also influences the expression and function of PD-1, and vice versa. This cross-talk between checkpoints adds layers of complexity to our understanding of immune modulation.

Mutual regulation by the PD-1/CD226/TIGIT/CD96 pathways.Fig. 1 Mutual regulation by the PD-1/CD226/TIGIT/CD96 pathways.1

Mutual Regulation of PD-1 and CTLA-4

PD-1 is primarily expressed on activated T cells, B cells, and myeloid cells, while CTLA-4 predominantly resides in regulatory T cells (Tregs). Their signaling pathways converge on dampening T cell activity, but they employ distinct mechanisms.

  • PD-1 exerts its effects during the effector phase of the immune response, inhibiting T cell activation and cytokine production when it binds to its ligands, PD-L1 and PD-L2.
  • CTLA-4 primarily acts during the priming phase of T cell activation by outcompeting CD28 for binding to B7 molecules on antigen-presenting cells (APCs).

The mutual regulation between PD-1 and CTLA-4 is a dynamic process.

  • Studies have shown that PD-1 can upregulate the expression of CTLA-4 on Tregs, further enhancing their suppressive function.
  • CTLA-4 engagement can lead to the upregulation of PD-1 on T cells, contributing to T cell exhaustion.

Mutual Regulation of TIM-3 and PD-1

TIM-3 is expressed on exhausted T cells and plays a pivotal role in dampening their function. PD-1 and TIM-3 often co-exist on exhausted T cells, and their interaction can have profound implications for immune responses in cancer.

Recent studies have unveiled a compelling connection between PD-1 and TIM-3.

  • It has been observed that the co-expression of PD-1 and TIM-3 on T cells marks a population of cells with particularly severe exhaustion. This co-expression suggests a synergistic effect, where the presence of both checkpoints leads to a deeper state of T cell dysfunction.
  • The interaction between PD-1 and TIM-3 can create a "double-negative" feedback loop, amplifying T cell exhaustion.

Mutual Regulation of LAG-3 and PD-1

LAG-3 is expressed on activated T cells and regulatory T cells and is involved in modulating T cell responses. The mutual regulation of LAG-3 and PD-1 is a topic of growing interest in the field of immunotherapy.

  • Research has shown that the co-expression of LAG-3 and PD-1 on T cells is associated with more severe T cell dysfunction and immune evasion in cancer. These co-expressing cells exhibit a higher degree of exhaustion and reduced effector functions, making them challenging targets for single checkpoint blockade therapies.
  • The combination of LAG-3 and PD-1 blockade has shown promising results in preclinical studies and early-phase clinical trials. This combination appears to have a synergistic effect in reinvigorating T cell responses and enhancing antitumor immunity.

As researchers delve deeper into the intricacies of these interactions, we can expect the development of tailored combination therapies that harness the power of mutual regulation to enhance antitumor immunity.

At Creative Biolabs, we remain dedicated to advancing the field of immunotherapy through cutting-edge research and innovative solutions. Stay tuned for more updates on the exciting developments in the world of immune checkpoint modulation.


  1. Shi, Tao, et al. "Cancer immunotherapy: a focus on the regulation of immune checkpoints." International journal of molecular sciences 19.5 (2018): 1389.

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