Exam 1: Antigen Processing and T-cell Development Flashcards

1
Q

Target Cells

vs

APC’s

A

Professional antigen-presenting cells (APCs) display peptides on class II MHC molecules to CD4+ helper T-cells.

Target cells present peptides on class I MHC to CD8+ cytotoxic T-cells.

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2
Q

Cytosolic Pathway

Characteristics

A
  • Class I MHC presents endogenous antigens
  • Peptides can be any protein which have been synthesized in the cytoplasm of the cell:
    • viral components
    • intracelluar bacteria
    • altered self proteins
    • normal self proteins
      • typically does not trigger an immune response
  • Recognized by CD8+ cytotoxic T-cells
  • Site of activity is the target cell
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3
Q

Cytosolic Pathway

Mechanism

A
  1. Endogenous Ag degraded within the cytoplasm by a proteasome.
  2. Cytosolic peptides trasported by TAP (transporter associated with atigen processing) into the RER.
  3. Class I MHC α-chains synthesized and associated with β2-microglobulin through chaperone-mediated interactions in RER.
  4. Class I MHC loaded with peptide and moves from RER to Golgi to plasma membrane.
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4
Q

Endocytic Pathway

Characteristics

A
  • Class II MHC binds peptides which have been phagocytized or endocytosed from the extracellular environment.
  • Any protein which was synthesized elsewhere and subsequently taken in by APC could be expressed on MHC II.
  • If protein seen as “non-self” it can be recognized by CD4+ helper T-cells.
  • Once activated Th cells will synthesize cytokines that regulate cellular & humoral immunity.
  • Site of activity is the professional APC.
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5
Q

Endocytic Pathway

Mechanism

A
  1. Exogenous Ag taken up by phagocytosis, endocytosis, or pinocytosis depending on the APC.
    • Waits for MHC II molecules
  2. Class II MHC α- and β-chains synthesized in the RER and associated with the invariant (Ii)-chain
    • guides MHC where it needs to go
    • blocks the binding grooves so peptides cannot be loaded
  3. αβIi complexes transported through Golgi to endosomes and lysosomes
  4. Invariant chain progressively degraded ultimately leaving only CLIP (class II-associated invariant chain peptide) in the peptide binding groove
  5. CLIP removed and exogenous peptide from endosome or lysosome added
  6. Peptide-loaded class II MHC transported to plasma membrane
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6
Q

Antigen-processing Pathways

Summary

A

If a peptide is recognized as foreign on class I MHC by CD8 T-cells it signals that there is a problem within this cell ⇒ kill the cell.

If a peptide is recognized as foreign on class II MHC by CD4 T-cell it signals that there is a problem within the body ⇒ produce cytokines to help activate/modulate the immune system.

All antigens must eventually go on MHC II to activate a proper immune response.

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7
Q

Vesicular Pathogens

A
  • Some microbes have evolved to resist the microbicidal activites of phagocytes.
    • Ex. Tuberculosis, protozoa
  • Can survive and replicate within the phagolysosomes.
  • Since pathogens exist in the source compartment for class II MHC, peptides are located onto MHC II despite being produced within the cell.
    • Stimulates IFN-γ production by CD4 T cells.
  • IFN-γ promotes macrophage activation and killing.
    • Stimulates granuloma formation if cannot kill.
  • Some of these microbes may enter the cytoplasm of infected cells and divide there so loaded onto MHC I.
    • When cytotoxic cells try to kill them may just distribute pathogen upon lysis.
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8
Q

Issues with MHC

A

MHC unable to discriminate between foreign and self antigens.

  • Concentration of self-proteins will outnumber microbial or “altered self” antigens.
    • Virally infected cells make IFN α/β within hours of infection.
    • Stimulates MHC I production
    • High concentration of viral Ag allows Ag loading onto newly synthesized MHC I ⇒ Activates CD8 T-cells.
  • MHC molecules are constantly displaying self-antigens.
    • TCR has induced tolerance which prevents autoimmunity.
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9
Q

T-cell Development

Overview

A
  1. Bone marrow progenitor cells (Pro-T cell expressing CD2) migrate to the thymus gland
  2. Immature cells enter the cortex and mature as they travel towards the medulla.
  3. Mature naive T cells leave thymus through peripheral blood circulation and travel to 2° lymphoid organs
  4. Cells populate 2° lymphoid organs where they can encounter Ag and exert effector functions
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10
Q

Thymus

A
  • Primary lymphoid organ for T-cells
    • Shrinks after puberty or corticoid exposure
  • As thymocytes (developing T-cells) move from cortex to medulla they become more mature and express different surface markers
  • Direct contact with:
    • Non-lymphoid thymic stromal cells
      • Soluble and membrane-bound factors
    • Bone marrow derived interdigitating dentritic cells
      • Aids thymic education (selection)
  • Thymic microenvironment directs T cell development through direct cell-cell contact and cytokines
    • Which cytokine they encounter determines the type of T cell they become
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11
Q

T-cell Differentiation

A
  1. Pro-T cells (CD2+, CD7+) migrate from bone marrow to thymic cortex.
  2. TCR rearrangement forms pre-T cells.
    • Express low levels of TCR and CD3.
    • No CD4 or CD8 yet = double negative cells (TCR+low, CD3+, CD4-, CD8-)
  3. Following TCR expression, both CD4 and CD8 are coexpressed to produce double positive cells (TCR+low, CD3+, CD4+, CD8+)
    • Thymic education occurs
      1. Positive selection
        • Ensures that T cell can bind peptides on MHC molecules
        • Bindings results in a “to live” signal
        • Can only recognize Ag when bound to the same MHC encountered in the thymus = MHC restriction
      2. Negative selection
        • Removes cells that recognize self-peptides bound to MHC
        • Autoreactive cells get a “to die” signal
        • Failure results in potentially auto-reactive T cells
  4. Cells which survive selection down regulate either CD4 or CD8 to become single positive cells.
  5. These cells upregulate expression of αβ TCR molecules.
    • Become either mature Th cells or mature Tc cells.
  6. Mature naïve T cells enters circulation and travel to 2° lymphoid organs or back to bone marrow.
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12
Q

MHC Polymorphisms

A
  • Allelic forms of MHC I & II expressed determines which peptides can be presented.
    • Also determines which T cells survive positive and negative selection.
  • Suggests that there is a genetically predetermined capacity to react immunologically against a given immunogen.
  • Plays a role in individual immune responses leading to resistance or susceptibility to infection & autoimmunity.
  • Usually only a few epitopes from any antigen or pathogen can be presented effectively to a T cell.
    • Expression of multiple MHC genes increases likelihood of success.
  • Polymorphism provides protection for species at large.
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13
Q

Autoimmunity

A

MHC alleles have been linked to autoimmune disease.

No HLA allele associated with 100% of cases so probably only one of the factors involved.

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