12. Immune Checkpoint Receptors

Question 1

Immune checkpoint molecules are BLANK receptors expressed on immune cells that triggers BLANK signalling pathways

Answer 1

Immune checkpoint molecules are INHIBITORY receptors expressed on immune cells that triggers IMMUNOSUPPRESSIVE signalling pathways

Question 2

Inhibitory receptors are essential for limiting effector immune responses to prevent collateral tissue damage and restore tissue tolerance
TRUE OR FALSE

Answer 2

TRUE

Question 3

CTLA-4 (Cytotoxic T Lymphocyte Antigen 4):

Answer 3

• Immune Checkpoint Receptor
• Only expressed on activated T cells
• Immunoglobulin domain-containing transmembrane protein
• Competes with CD28 to bind B7 ligands, CD80 and CD86
• Signals cell-intrinsically to reduce TCR and CD28 signalling
• Reverse signals through CD80/CD86 to reduce co-stimulation

Question 4

PD1 (Programmed Cell Death Protein 1):

Answer 4

-Immune Checkpoint Receptor
-Expressed on T cells, B cells, NK T cells, DCs, and activated monocytes
-Up-regulated upon TCR activation (and is persistent in the presence of constant TCR ligation)
-Has 2 ligands: PDL1 and PDL2
PDL1 is constitutively expressed on T cells, B cells, macrophages, and dendritic cells
PDL2 also appears to contribute to PD1-mediated inhibition (but less is known about PDL2)

Question 5

LAG-3 (Lymphocyte Activation Gene 3):

Answer 5

• Expressed on T cells
• Can interact with MHCII
• KIEELE motif in cytoplasmic tail of LAG-3 is important for its function (but unknown how it signals)
• LAG-3 and PD1 are often co-expressed on exhausted T cells and combined blockade cures mice of most tumours

Question 6

FGL1 (Fibrinogen-Like Protein 1):

Answer 6

• An immune inhibitory ligand of LAG-3
• Member of the fibrinogen protein family, which is expressed at low levels in the liver under normal circumstances
• Highly expressed in many types of cancer, such as prostate cancer
• Antibodies to LAG-3 are NOT protective against tumours in FGL1-/- mice

Question 7

TIGIT (T Cell Immunoreceptor with Ig and ITIM Domains):

Answer 7

Receptor expressed on T cells, only after activation

• Binds CD155 with high affinity
• Binds CD112 with lower affinity
• Binding of TIGIT to CD155 prevents binding of CD155 with CD226 on the T cell, thus preventing downstream activatory signals