Cell-Mediated Immunity

What are the origins of Signal 3

What are the factors influencing the polarization of Th cells

Factors:

• Cytokine milieu determined by preceding innate immune response (signal 3).

• Cytokines produced by APCs (signal 3).

• The abundance of specific peptide:

• The affinity of the peptide-MHC complex for the TCR.

Describe TH1

• Functions

• Describe cross presentation

  • What is it?

  • Mech

• Describe CD8+ T cells

  • Function

  • Mech

• Describe Macrophages

  • Req. for act.

  • effect of act.

  • What happens if act. does not occur

TH1

Functions:

• Activate CD8+ T cells (AKA cytolytic T cells (CTLs)

• Activate Macrophage killing functions

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Cross Presentation

• What is it

  • the process in which DC changes from MHC Class II to I to act. CTLs

• Mech.

  • 1. CD4+ T Cell is Activated

  • 2. Activated CD4 T Cell “Gives DC License” to Activate CD8 T Cell

    • Binding of CD40L(T) - CD40(DC)

    • endocytosed pathogen → proteasome → endogenous processing pathway → MHC class 1

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Cytotoxic CD8+ T Cells

• Function:

  • Protection against viruses and tumors

• Mechanism:

  • CTL Fas ligand (FasL) binds to Fas on target cell → apoptosis

  • releases cytotoxins → target dies by necrosis

    • Perforin:

      • form pores in membrane

    • Granulysin:

      • disrupt cell membrane integrity

    • Granzyme:

      • serine protease

      • enters via pores → chops up target cell proteins

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Macrophages:

• Mac Act. requirements (from Th1):

  • (IFNg)

  • CD40 ligand

• Effects of Activation:

  • phago/lysosome fusion more efficiently

  • Increased expression of CD40

  • Secretion of TNFa

  • Highly reactive and microbicidal molecules are produced:

    • Oxygen radicals

    • Nitric Oxide

    • Proteases

• Failure to Activate:

  • Granuloma formation,

    • when lymphocytes surrounds the macrophages w/ the antigen

    • EX: M. tuberculosis infections

  • Consequences:

    • Caseous Necrosis can occur @ center of tubercular granuloma,

    • bacilli can replicate → escape granuloma → disseminate.

Describe Th2

• Function

• Mech

Function:

• Act. B cell Dif. → Plasma Cells

  • often labeled “Humoral”

  • Th1 can also do this, but tend to induce human IgG2 isotype antibodies

    • very good at opsinization and complement activation.

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Mech:

• Th2 only act. B cells if BOTH recognize same specific antigen (cognate interaction)

  • specific epitopes can be dif. but the antigen must be the same

• Th2 → upregulates CD40L + produce IL-4/5 → B cell clonal expansion

  • Il-5 → B cell dif. to plasma cells

Describe Th9

• Function

• Explain how Th9 is good and bad

Function:

• Augment Immune Responses

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Th9 = good and Bad

• Bad:

  • enhances antibody production + increases immune cell activity in respiratory tract → asthma

  • increases intestinal permeability + enhance pro-inflammatory Th cell responses in colon

• Good:

  • potent antiparasite activity

    • increases cell infiltration and enhances leukocyte functions.

  • augment anti-tumor immune activity.

Describe Th17’s function

Functions:

• major role in autoimmunity

  • multiple sclerosis

  • inflammatory bowel diseases

• activate tissue cells

• recruit neutrophils.

• important defense against extracellular bacteria

Describe Th22

• Function

• Mech

Function:

• remodeling of epidermis

• reinforcement Of barrier function

Describe Tfh

• Function

• Mech

Function:

• helps in Selection of high affinity B cell clones after Somatic hypermutation

  • makes sure these mutations doesn’t produce a worst B Cell

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Mech:

• + reaction:

  • BCR crosslinking → presentation to Thf cell → Thf sends signals to B cells → Proliferation + differentiation to plasma cells

• - reaction:

  • low/no binding to ag; no presentation to Thf → dies

Describe Treg

• Function

• Creation

• Mech.

• Function:

  • Block dendritic cell function

  • Suppress the responses of other effector T cells

  • Suppress autoreactive T cells

    • Treg binds to same APC → suppress the autoreactive T cell

• Creation:

  • “Natural” or ”Thymic” tTreg : formed in thymus

  • “Induced” or “Peripheral” pTreg: differentiate in periphery from naïve CD4+ T cells

• Mechanisms:

  • Targets DCs

  • Secrete inhibitory cytokines

  • Induce cytolysis

  • Compete for DCs against Teff

  • Metabolic disruption of Teff

Describe the Mech. of improving Teff migration from Lymph node → infection/inflammation site

Mech. of improving Teff migration from Lymph node → infection/inflammation site

• Upregulation of chemokine receptors

• Downregulation of L-selectin

  • so that activated cells can exit lymphoid organ.

• Upregulation of specific adhesion molecules

  • Ex: Integrin a4b1 - aka VLA-4

  • increases adhesion to endothelial cells in Blood vessel lumen

• Upregulation of CD44

  • receptor for hyaluronic acid

    • tissues contain high levels of this

    • Allows Teff to be retained

Draw out how the innate and adaptive immunity work together