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. Author manuscript; available in PMC: 2019 Jan 3.
Published in final edited form as: Blood. 2017 Nov 8;131(1):58–67. doi: 10.1182/blood-2017-06-741033

Figure 2. CTLA-4 function and the impact of immune checkpoint blockade.

Figure 2

(A) In health, regulatory T cells express CTLA-4, which binds CD80 and CD86 expressed on antigen presenting cells (APCs). CTLA-4 binds to CD80 and CD86 with higher affinity and avidity than does CD28, preventing Tcon stimulation through CD80/CD86 interaction with CD28. Removal of CD80/CD86 ligands by trans-endocytosis results in impaired costimulation of T cells via CD28, resulting in immune regulation. (B) When the immune system is stimulated in the presence of inflammatory/innate immune stimuli, APCs up-regulate the expression of CD80/CD86 overcoming their control by Treg, enabling co-stimulation and the proliferation of T cells. (C) In the tumour microenvironment, CD80/CD86 are controlled by Treg and the abundance of Treg leads to the suppression of immune responses. (D) Anti-CTLA-4 antibodies bind to CTLA-4 molecules with high affinity leading to Treg depletion or functional blockade resulting in enhanced T cell activation and immunological responses to cancer. The impacts of CTLA-4 blockade can be mediated by a variety of mechanisms: prevention of trans-endocytosis increasing CD80/CD86 levels on APCs, direct Treg cytotoxicity and antibody dependent cellular cytotoxicity mediated by FcR-IV expressing intra-tumoural macrophages. NB only CD80 is shown here for clarity.