What is the Difference Between CTLA-4 and PD-1

The key difference between CTLA-4 and PD-1 is that CTLA-4 is a negative regulator of T-cell immune function that is thought to suppress T-cell function early in an immune response, while PD-1 is a negative regulator of T-cell immune function that is thought to suppress T-cell function late in an immune response.

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) are two different negative regulators of T-cell immune function. Other than inhibiting immune responses, CTLA-4 and PD-1 also have antitumor responses. CTLA-4 is primarily functioning in lymph nodes, while PD-1 is primarily functioning in peripheral tissues. Ipilimumab, nivolumab, and pembrolizumab are drugs that can inhibit the functions of CTLA-4 and PD-1. These are mainly used in cancer treatments such as melanoma and non-small cell lung cancer.

CONTENTS

1. Overview and Key Difference
2. What is CTLA-4  
3. What is PD-1
4. Similarities – CTLA-4 and PD-1
5. CTLA-4 vs. PD-1 in Tabular Form
6. Summary – CTLA-4 vs. PD-1

What is CTLA-4?

CTLA-4 is a molecule that decreases the function of T cells. CTLA-4 is also known as CD152 (cluster of differentiation 152). It is a protein receptor that normally functions as an immune checkpoint. CTLA-4 downregulates immune responses as well. CTLA-4 is a protein encoded by the CTLA-4 gene and contains an extracellular V domain, a transmembrane domain, and a cytoplasmic tail.

CTLA-4 was first identified in 1991. CTLA-4 is homologous to the T-cell co-stimulatory protein called CD28. CD28 transmits a stimulatory signal to T cell and enhance T cell immune function. Both CTLA-4 and CD28 bind to CD80 and CD86 (B7-1 and B7-2, respectively) on antigen-presenting cells. But CTLA-4 binds to CD80 and CD86 with greater affinity than CD28. This enables CTLA-4 to outcompete CD28 for its ligands. Thereby, CTLA-4 transmits an inhibitory signal to T cells and downregulates T cell function ultimately. Furthermore, variations in the CTLA-4 gene have been associated with Type 1 diabetes, Graves’ disease, Hashimoto’s thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy, primary biliary cirrhosis, and other autoimmune diseases such as rheumatoid arthritis,  autoimmune thyroid disease, and multiple sclerosis.

What is PD-1?

Programmed cell death protein 1 (PD-1) is an inhibitory receptor protein T cells express during activation. It is also a protein found on the surface of B cells. PD-1 is a protein in humans which is encoded by the PDCD1 gene. Moreover, it is a cell surface receptor that belongs to the immunoglobulin superfamily. PD-1 is a negative regulator of T-cell immune function that is thought to suppress T-cell function late in an immune response. PD-1 primarily functions in peripheral tissues. This protein down-regulates the immune system, and this prevents autoimmune diseases. However, it can also prevent the immune system from killing cancer cells.

PD-1 is an immune checkpoint and guards protein against autoimmunity through two mechanisms. In the first mechanism, PD-1 promotes apoptosis or programmed cell death of antigen-specific T-cells in lymph nodes, whereas, in the second mechanism, PD-1 reduces apoptosis in regulatory T cells (anti-inflammatory or suppressive T cells that maintain tolerance to self-antigens and prevent autoimmune disease). Furthermore, blocking PD-1 is currently used to treat diseases such as cancer, HIV, and Alzheimer’s disease.

What are the Similarities Between CTLA-4 and PD-1?

• CTLA-4 and PD-1 are two different negative regulators of T-cell immune function.
• Both are immune checkpoints and guard proteins.
• Both are cell surface receptors of the immunoglobulin superfamily
• They are extremely important to control autoimmunity.
• Ipilimumab, nivolumab, and pembrolizumab are drugs that can inhibit the functions of CTLA-4 and PD-1.

What is the Difference Between CTLA-4 and PD-1?

CTLA-4 is a negative regulator of T-cell immune function that is thought to suppress T-cell function early in an immune response, while PD-1 is a negative regulator of T-cell immune function that is thought to suppress T-cell function late in an immune response. Thus, this is the key difference between CTLA-4 and PD-1. Furthermore, CTLA-4 was first identified in 1991, while PD-1 was first identified in 1992.

The infographic below presents the differences between CTLA-4 and PD-1 in tabular form for side-by-side comparison.

Summary – CTLA-4 vs. PD-1

Immune checkpoints are regulatory molecules of the immune system. These molecules are extremely important for self-tolerance, and they prevent the immune system from attacking one’s own cells indiscriminately. CTLA-4 and PD-1 are two immune checkpoints and guard proteins and are negative regulators of T-cell immune function. CTLA-4 is an immune checkpoint and guard protein that suppresses T-cell function early in an immune response, while PD-1 is an immune checkpoint and guard protein that suppresses T-cell function late in an immune response. So, this summarizes the difference between CTLA-4 and PD-1.

Reference:

1. “CTLA-4.” ScienceDirect Topics.
2.“PMC.” National Center for Biotechnology Information.

Image Courtesy:

1. “11 Hegasy CTLA4 PD1 Immunotherapy” By Guido4 – Own work (CC BY-SA 3.0) via Commons Wikimedia
2. “Negative, low and high PD-L1 expression by immunohistochemistry” By Müller T, Braun M, Dietrich D, Aktekin S, Höft S, Kristiansen G – Müller T, Braun M, Dietrich D, Aktekin S, Höft S, Kristiansen G (2017). “PD-L1: a novel prognostic biomarker in head and neck squamous cell carcinoma”. Oncotarget 8 (32): 52889-52900. DOI:10.18632/oncotarget.17547. PMID 28881780. PMC: 5581079.- (CC BY 3.0) via Commons Wikimedia