T Cell Activation and Effector Functions Flashcards

1
Q

T-Cell Activation

A

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:
    1. TCR engagementTCR: peptide + self-MHC
    2. Costimulatory signalCD28 (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
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2
Q

Antigen Sources

A
  • 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.
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3
Q

Professional APC’s

A
  1. Macrophages
    • exogenous Ag from phagocytosis
  2. B-cells
    • Ag binds Ab (BCR)
    • Clathrin coated vesicle endocytosed
    • Exogenous Ag ⇒ very homologous Ag due to BCR specificity
  3. 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
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4
Q

T-Cell Signaling

A

Common to both CD4 and CD8 T-Cells

  1. T cell receptor engagement results in clustering of multiple TCRs (#30-200), CD4/CD8 molecules, CD28, and other cell surface receptors.
  2. Transphosphorylation/activation of Lck and Fyn (protein tyrosine kinases)
  3. Activated Lck/Fyn phosphorylate ITAMS on CD3 and ζ (zeta) chains.
  4. ZAP70 (Zeta-associated protein tyrosine kinase-70) docks via ITAM-P.
  5. Lck phosphorylates ZAP70 leading to activation.
  6. ZAP 70 phosphorylates numerous proteins including phospholipase Cγ (PLCγ) and guanine nucleotide exchange facors (GEFs)
  7. 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.
  8. Induces transcription of many genes including IL-2 and IL-2 receptor α-chain.
  9. 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.
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5
Q

T-Cell

Clonal Proliferation

A

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.
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6
Q

Naïve T-cell

Circulation

A
  1. Enter the lymph node via peripheral blood through high endothelial venules (HEVs)
  2. Search for its MHC+peptide match in LN
  3. Exit via lymphatics → circulation → another LN to maximize opportunity for Ag+MHC recognition.
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7
Q

Lymph Node

Recruitment of Naïve T-cells

A
  1. 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
  2. Chemokine stimulation of T-cell → conformational change of LFA-1 (integrin) molecule → increased affinity of LFA-1 for its ligand ICAM-1
  3. LFA-1 on T-cells binds ICAM-1 on HEV leading to firm attachmentdiapedesis
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8
Q

Inflammatory/Infectious Focus

Recruitment of Activated T-Cells

A

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.

  1. Effector T-cell rolling mediated by P and E-selectins on the activated endothelium.
  2. 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
  3. LFA-1/VLA-4 on T-cells bind to ICAM1/VCAM-1 on endothelium promoting firm attachmentdiapedesis.
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9
Q

Effector T-Cell

Stimulation and Effector Functions

A

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
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10
Q

T-cell Lifecycle

Summary

A
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11
Q

Immune Response

Down Regulation

A

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

Within 1-2 weeks of clearance, the only remaining component of the immune response is a pool of memory cells.

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12
Q

Immunological Memory

A

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
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13
Q

Life of a T-cell

Summary

A

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.

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