T Cell Activation and Effector Functions Flashcards
T-Cell Activation
Naïve Tc and TH cells require two signs for activation:
- Naïve T cells “sample” MHC/peptide combinations through low affinity interactions mediated by adhesion molecules.
- Engagement of the TCR results in increased binding affinity of adhesion molecules
- Naïve T cells need two signals for activation:
- TCR engagement – TCR: peptide + self-MHC
- Costimulatory signal – CD28 (T-cell) : B7 (APC)
- Cells that receive only signal #1 become anergized.
- Facilitates extra-thymic self (& tumor) tolerance
Effector and memory T cells require only signal #1 for activation.
- Only requires TCR: peptide/MHC interaction but still prefers CD28:B7 interaction as well
Antigen Sources
- Immature dendritic cells and macrophages phagocytize the Ag in the tissue and carry it to the draining lymph node.
- Draining interstitial fluids carry Ag to dendritic cells, macrophages, and B-cells in the lymph node.
Professional APC’s
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Macrophages
- exogenous Ag from phagocytosis
-
B-cells
- Ag binds Ab (BCR)
- Clathrin coated vesicle endocytosed
- Exogenous Ag ⇒ very homologous Ag due to BCR specificity
-
Dendritic cells
- Most potent APC for naïve T cells
- Bone marrow derived
- Found in virtuall ALL tissues
- Langerhan cells = immature dendritic cell in skin
- Constantly phagocytose until a “danger signal” occurs
- Skin damage or infection
- PAMPs or DAMPS : PRR
- Danger signal causes cell to leave tissue and enter lymph node
- Matures ⇒ can endocytose or pinocytose but no longer phagocytic
- Increases MHC I and II expression
- Increases B7 expression
T-Cell Signaling
Common to both CD4 and CD8 T-Cells
- T cell receptor engagement results in clustering of multiple TCRs (#30-200), CD4/CD8 molecules, CD28, and other cell surface receptors.
- Transphosphorylation/activation of Lck and Fyn (protein tyrosine kinases)
- Activated Lck/Fyn phosphorylate ITAMS on CD3 and ζ (zeta) chains.
- ZAP70 (Zeta-associated protein tyrosine kinase-70) docks via ITAM-P.
- Lck phosphorylates ZAP70 leading to activation.
- ZAP 70 phosphorylates numerous proteins including phospholipase Cγ (PLCγ) and guanine nucleotide exchange facors (GEFs)
- PKCγ and GEFs both initiate a series of cascades leading to production of transcription factors (NFAT, NF𝛋B, and AP-1).
- Cyclosporin and FK506 block production of transcription factors by blocking calcinerin function = immunosuppresion.
- Induces transcription of many genes including IL-2 and IL-2 receptor α-chain.
- IL-2:IL-2 receptor activation key for T cell proliferation and differentiation.
- IL-2 and receptor alpha-subunit made within several hours after activation.
- Takes ~ 24 hours for each round of T cell division.
- T-cells say IL-2, I love you.
T-Cell
Clonal Proliferation
Fevery few T-cells will react against a single Ag, therefore, clonal proliferation must occur before there is a significant T cell response.
Mechanism of antigen-specific T cell amplification:
- IL-2 Receptor is a trimeric protein (α, β, and γ)
- β and γ chains are constitutively expressed on mature T cells.
- α-chain expressed on activated but not resting T-cells
- Trimeric complex needed for IL-2 binding and signaling at physiological cytokine levels.
- low affinity receptor = α
- intermediate affinity receptor = βγ
- high affinity receptor = αβγ
- IL-2 binding and IL-2R signaling leads to T cell proliferation.
- This significantly increases the number of T cells reactive to the threat/pathogen.
- Allows for greater effector activity.
Toxic shock syndrome
- Causes a cytokine storm resulting in a massive release of IL-2
- Able to active T-cells in an Ag-independent manner.
Naïve T-cell
Circulation
- Enter the lymph node via peripheral blood through high endothelial venules (HEVs)
- Search for its MHC+peptide match in LN
- Exit via lymphatics → circulation → another LN to maximize opportunity for Ag+MHC recognition.
Lymph Node
Recruitment of Naïve T-cells
-
Rolling is mediated by L-selectins on T-cell that bind to special siayl-Lewisx glycoprotein ligands (CD34) on HEV in LN.
- The L-selectin:CD34 ligand interaction targets naïve T-cells to LN
- Chemokine stimulation of T-cell → conformational change of LFA-1 (integrin) molecule → increased affinity of LFA-1 for its ligand ICAM-1
- LFA-1 on T-cells binds ICAM-1 on HEV leading to firm attachment → diapedesis
Inflammatory/Infectious Focus
Recruitment of Activated T-Cells
Following activation, proliferation, and differentiation - effector T-cells are free to migrate out of the lymph node.
Effector T-cells no longer express L-selectin and up-regulate other homing molecules to promote migration to site of infection.
- Effector T-cell rolling mediated by P and E-selectins on the activated endothelium.
- Chemokine stimulation of T-cell → conformation change of LFA-1 and VLA-4 molecules on T cell → increased affinity for ligands ICAM-1 and VCAM-1 on endothelium
- LFA-1/VLA-4 on T-cells bind to ICAM1/VCAM-1 on endothelium promoting firm attachment → diapedesis.
Effector T-Cell
Stimulation and Effector Functions
Effector T-cells smaple cells for MHC+peptide match.
Signal #1 through TCR leads to activation and effector functions.
(Effector T cells only require signal #1 for activation)
CD4 T-cells
- Cytokine production leads to:
- CD8 cell proliferation → defense against viruses & malignant cells
- Macrophage activation → intracellular bacteria
- NK cell function → viruses, malignant cells
- B cell proliferation / isotype switching → viruses (extracellular stages), bacteria (extracellular, helminthic parasites
CD8 T-cells
- Killing
- Serial killers (up to 1,000) cells via apoptotic death
T-cell Lifecycle
Summary
Immune Response
Down Regulation
T-cell activation and proliferation is dependent upon antigen stimulation.
- Clearance of threat
- loss of T cell activation
- stop of IL-2 and IL-2R synthesis
- loss of survival factors
- death by apoptosis
- Down modulatory cytokines
- TGF-β made by regulatory T-cells
- Inhibits the immune response
- TGF-β made by regulatory T-cells
Within 1-2 weeks of clearance, the only remaining component of the immune response is a pool of memory cells.
Immunological Memory
Memory allows the immune system to respond more rapidly and effectively to previously encountered threats or pathogens.
Goal: provide protective immunity (immunity to reinfection) so that an absent, subclinical, or mild infection occurs upon subsequent exposure.
Mechanisms:
- Pre-existence of a clonally expanded population.
- Memory cell fuctionally different
- Faster response
- naïve cells take 4-5 days
- memory cells take 1-2 days
- Better response
- T-cells: more complex cytokine profile
- B-cells:
- different isotypes: IgG, IgA
- higher affinity
- greater quantities
- Lower Ag titer required for activation
- Faster response
Life of a T-cell
Summary
Naïve T-cells wait in the periphery for specific Ag stimulation.
Naïve T-cells can recirculate for a year or so waiting for activation.
Actual fate of these cells is unknown.
Unclear if body produces subclinical Ag levels so memory cells stimulated and life extended.