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Arrow 1 = direct activation

Arrow 2 = release of cytokines to cause further activation

All T cells have:  CD3, TRC, CD28

T helper cells also have: CD4 (not CD8)

Cytotoxic T cells and T Suppressor cells also have: CD8 (not CD4)

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Perforin = polymerizes to form a pore in target membrane

Granzymes = serine proteases, which activate apoptosis once in the cytoplasm of the target cell

Granulysin = induces apoptosis

CD4⁺ Helper T Cell

• Th1 produce IFN-γ, TNF-β (activate macrophages and cytotoxic T cells) and IL-2 primarily in response to intracellular (viral/bacterial) infection
• Th2 produce IL-4, IL-5, IL-6, IL-10, IL-13 (activate B cells) primarily in response to extracellular (bacterial, viral or paracitic) infection

CD8⁺ Cytotoxic T Cell

• Kills foreign or abnormal cells (viral-infected or rumor cells)

CD8⁺ Suppressor T Cell

Critical to health

As T and B lymphocytes mature within the thymus or bone marrow, those with receptors that react strongly wit the body's own antigens are either killed or self destruct, while less reactive, or low-affinity, immune cells survive

Second signal is important for maintaining self vs. non-self recognition

Without the ability to recognize self vs. non-self, autoimmunity would result

CD28 (always present) on T cell binds with B7 (presnt on antigen presenting cell when antigen in non-self) on APC as a second signal required to induce an immune response -- regulation by negative control mechanism: B7-CD28 interaction activates T cell → CD152 induced in T cells upon repeated CD28 activation → B7-CD152 interaction downregulates T cell

Small glycoproteins, which act as local messengers by binding to high affinity surface receptors.  Most cells of the body produce cytokines.  They are important mediators of cell biology and make significant contributions to inflammatory responses.  Cytokines have several functions including initiation and maintenance of immune and inflammatory responses and regulation of growth and differentiation of cells.

Produced predominantly by activated immune cells such as microglial cells and are involved in the amplification of inflammatory reaction.  These include IL-1, IL-6, TNF-α, and TGF-β.

• have pleiotropic effects - multiple activites can be caused by a single cytokine
• the classical proinflammatory cytokines are TNF-α, IL-1β, and IL-6
• TNF-α, IL-1β, and IL-6 act on the hypothalamus to induce fever and on the liver to induce production of acute-phase proteins (e.g. C-reactive protein, serum amylois A, fibrinogen, mannose binding protein, complement components)
• TNF-α and IL-6 act on vascular endothelial cells and macrophages to induce secretion of colony stimulating factors (CSFs) that subsequently act on bone marrow to increase white blood cells
• TNF-α and IL-1β act on vascular endothelial cells to increase both vascular permeability (for leukocyte migration) and expression of cell adhesion molecules (for rolling and firm adhesion of leukocytes)

Cell Source:

• Monocytes
• Macrophages
• Fibroblasts
• Epithelial cells
• Endothelial cells
• Astrocytes

Cell Target:

• T cells; B cells
• Endothelial cells
• Hypothalamus
• Liver

Pimary Effects:

• Costimulatory molecule (in T and B cells)
• Activation of endothelial cells (inflammation)
• Fever (from the hypothalamus)
• Actue phase reactants (produced by the liver)

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Cell Source:

• T cells (TH1)
• NK cells

Cell Target:

• T cells; B cells
• Monocytes

Pimary Effects:

• Growth of T and B cells
• Activation of Monocytes

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Cell Source:

• T cells (TH2)

Cell Target:

• Naïve T cells
• T cells
• B cells

Pimary Effects:

• Differentiation of naïve T cells into Th2 cells
• Growth of T cells
• Activation and growth of B cells (plus isotype switching to IgE)

Cell Source:

• Macrophages
• Epithelial cells
• Platelets

Cell Target:

• Neutrophils

Pimary Effects:

• Activation and chemotaxis of neutrophils

Cell Source:

• T cells (TH2)***
• B cells
• Monocytes

Cell Target:

• Macrophages
• T cells (TH1)
• NK cells
• B cells

Pimary Effects:

• Inhibits APC activity and cytokine secretion of macrophages
• Inhibits cytokine production in T cells (TH1)
• Simulates B cells, inducing class II MHC and promoting gowth

Cell Source:

• T cells
• NK cells

Cell Target:

• Monocytes
• Endothelial cells
• Many tissue cells; especially macrophages

Pimary Effects:

• Activation of monocytes
• Activation of endothelial cells
• Increased class I and II MHC in tissue cells

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Cell Source:

• Macrophages
• T cells

Cell Target:

• T cells; B cells
• Endothelial cells
• Hypothalamus
• Liver

Pimary Effects:

• Costimulatory molecule (in T and B cells)
• Activation of endothelial cells (inflammation)
• Fever (from the hypothalamus)
• Actue phase reactants (produced by the liver)

IL-2 + IL-4 + IL-5 = B cell proliferation

IL-2 + IL-4 + IL-5 = IgM expression

IL-4 + IL-6 + IL-2 + IFN-γ = IgG expression

IL-5 + TGF-β = IgA expression

IL-4 = IgE expression (inflammatory response and type I hypersensitivity)

Interleukins bond directly to switch regions in the DNA (to cause the isotype switch)

TH1 → IL-2, IFN-γ, TNF-β

TH2 → IL-4, IL-5, IL-6, IL-10

Memory T Cell → IL-2

Viruses (and certain intracellular bacteria) induce IL-12 release from APC that activates NK cells to produce IFN-γ, which induces naïve T cells to differentiate into TH1 cells

Other pathogens do not induce IL-12 release but cause release of NK cell IL-4, which induces  naïve T cells to differentiate into TH2 cells

Different Stimuli Elicit TH1 or TH2 Types of Immune Responses

Intracellular pathogens (viruses, mycobacteria) and tumors → TH1 response

Extracellular pathogens (bacteria, fungi, and parasites) and allergens → TH2 response

TH1 ← IL-12, IFN-γ, intracellular pathogen, low antigen dose, systemic immunization

TH2 ← IL-10, IL-4, extracellular pathogen, high antigen dose, mucosal immunization

100 "variable" alleles, 20 "diversity" alleles, 6 "j" alleles, and 1 "constant" allele

Process:  D joins J, V joins D, C joins VDJ

Similar to heavy chain, but no "d" alleles

two basic types of light chains:  kappa and lambda

Role of Cytokines in Regulating Ig Isotype Expression

Calor = heat

Rubor = redness

Tumor = swelling

Dolor = pain

(Loss of function)

Inflammation can be a result of irritation, injury, or infection.

• LPS actively released from gram negative bacteria or lysed bacteria
• IL-1 or TNF released by damaged tissue cells of many types
• Affects hypothalamus by increasing metabolis and constricting blood vessels (reducing peripheral blood flow and loss of heat through the skin)
• Effect on bacteria is to inhibit growth due to the higher temperature
• Can have either a genral fever or a local increase in temperature

Isolating the damaged area

Mobilizing effector cells and molecules to the site

In the late stages--promoting healing

Cytokines (IL-1 and TNF-α)

Complement (C3a, C5a, and C4a)

Both cause increased vascular permiability resulting in fluid leakage and cells leaking out from the endothelial line of the blood vessel; this results in swelling, redness, heat, and pain.

IL-1 and TNF actiave endothelial cells causing them to express selectins such as intracellular adhesion molecule (ICAM) and vascular adhesion molecule (VCAM).

IL-8 and MIP-1 activate PMN causing them to express leukocyte adhesion molecules including a number of integrins.

The PMN bind to the endothelial cells in the vasculature and ultimately undergo diapediasis.