Chapter 5: T-Cell Mediated Immunity

T-Cell Activation

• Multiple TCRs need to be triggered for T cell activation to occur (high avidity)

• CD3 and zeta produce the same signals in all clones

LFA-1

A type of intergrin proteins in T cell that bind to ICAM-1 on APC for adhesion

CD28

Receptor on T-cells that binds to B7 costimulation for sufficient T cell activation

CTLA-4 & PD-1

• Inhibitory receptors of T cells, prevent immune response against self antigens

• Compete with CD28 for binding of B7

Lck

• Protein tyrosin kinase

• Non-covalently bind to CD4/CD8 coreceptor

• When MHC binds to coreceptor, it phosphorylates ITAM of CD3 and zeta chain

ZAP-70

• Phosphorylated ITAM on zeta, become active by Lck phosphorylation

• Phosphorylates PLC-gamma

Phospholipase-C Gamma (PLCγ)

• Phosphorylated by ZAP-70

• Enzyme that facilitates: PIP2 → IP3 + DAG

Inositol 1,4,5-triphosphate (IP3)

Releases calcium from ER to cytosol to activate enzyme calcineurin

Calcineurin

Dephosphorylates transcription factor NFAT

NFAT

• Activated by calcineurin

• Migrates from cytosol to nucleus and supports transcription of IL-2

Cyclosporine

• Immunosuppressive drug that prevent graft rejection

• Inhibits calcineurin phosphatase activity → suppress NFAT

Diacylglycerol (DAG)

Activates protein kinase C (PKC)

Protein Kinase C (PKC)

• Phosphorylates inhibitor κB

• nuclear factor-κB is released and move into nucleus

GTP-Binding Ras/Rac Protein

• Exchanges GDP for GTP on Ras & Rac

• These enzymes activate kinases ERK & JNK

ERK & JNK

• Kinases that activated by Ras/Rac GTP

• Formation of transcription factor AP-1, which enters nucleus and enhances transcription of T cell genes

Phosphatidylinositol-3 Kinase (PI-3)

Phosphorylates PIP2 → PIP3

Phosphatidylinositol-3,4,5-triphosphate (PIP3)

• Converted by PI-3 kinase

• Activates serine-threonine kinases Akt, and mTOR that promotes cell survival

ATP Metabolism in T Cell

• Naive T cell is resting so it has low glucose uptake. Generate ATP via oxidative phosphorylation in mitochondria

• Activated T cell requires high glucose uptake, ATP via anaerobic glycolysis

Interleukin-2 (IL2)

• Autocrine secreted by activated T cell

• Naïve T cells: only β and γc chains → low-affinity IL-2R

• Activated T cells: produce α chain → high-affinity IL-2R

• Stimulates survival and proliferation of T-cells

Clonal Expansion of T Cells

• Cytotoxic T cells expand 1000 times more than HTL

• CD8 functions by direct contact whereas CD4 secrete cytokines

CD40 Ligand

• Expressed when T cells activated via CD28-B7 complex

• Most important surface protein of effector HTL cells that makes APC better at stimulating by binding to CD40 on B cells, macrophages, dendritic cells

Migration of T Cell

• Naive T cells migrate between blood and PLO (lymph, spleen, MALT) until they encounter DC that displays Ag

• Effector cells: migrate to sites of infection

Naive T Cell Migration

• Express receptor L-selectin and chemokine receptor CCR7

• Enter LN through high endothelial venules (HEV), once entered lymph node retains the cells in paracortex (T-zone) due to expression of CCR7 & L-selectin

High Endothelial Venules (HEV)

• Lined with endothelial cells that express lectins (carbohydrate ligands) that bind to L-selectin on naive T cells

• Also display chemokines that get recognized by CCR7 (transduces signals to activate integrin)

Sphingosine-1-Phosphate (S1P)

• Higher levels in blood than inside lymph node

• When naive T cells in the LN, the low-S1P environment induces receptor S1PR1 to exit LN toward higher concentration via efferent vessel

• If naive cells encounter Ag, the S1PR1 is suppressed temporarily so the cells stays longer to undergo expansion and differentiation.

Naive vs Activated T Cell Receptors

• Naive has L-selectin receptor, but activated cell has E and P ligands

• Naive has CCR7 receptor, but activated cell has CXCR3 receptor