Cell-mediated immunity - Northern Arizona Universityfpm/immunology/lectures/Chapter014.pdf · - DTH is a second major form of cell-mediated immunity. - As with humoral immunity and

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Chapter 14

Cell-Mediated Effector Responses

Cell-mediated immunity

Effector role – detect and eliminate cells infected with intracellular pathogens

Two types:

1) Cytotoxic T cell response: - Cytotoxic T cells (CTLs) to kill virus-

infected and altered self-cells.

- NK cells and Macrophages

2) Delayed-type hypersensitivity (DTH): CD4 T cells that activate macrophages to enhance killing of intracellular

bacteria.

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CD2 (LFA-3) and LFA-1 (ICAM-1)

Naïve VS Effector cells The CTL response

Mediated by CD8+ cytotoxic T lymphocytes.

- CD8+ T cells that have not yet seen antigen are not cytotoxic - they

are referred to as precursor-CTL (CTL-P).

In order to become cytotoxic effector cells, CTL-P must:

- recognize antigen presented on class I MHC- express IL-2 receptors

- receive IL-2 (usually from a helper T cell)- proliferate

- differentiate into effector CTL

FIG 14-1

NOTE:

Expression of IL-2

receptors occurs only after CTL-P (precursor)

activation by antigen.

IL-2 from helper T cells is usually required

before CTL-P can

proliferate and differentiate into

effector CTL (though Ag-activated CTL-P can

produce some IL-2).

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Memory CTL-Ps secrete enough IL-2 for

own proliferation

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Th cells provide IL-2 for proliferation of

naïve CTL-Ps Killing by CTLs

• Lytic activity mediated by Perforin and

Granzymes

• Fas-mediated

• Working together or independently

Fig 14-9

The two pathways of CTL-mediated killing:

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1) Effector CTL form tight conjugates with target cells. Contents of CTL cytoplasmic granules are released into the intercellular space. These kill

the target cell.

2) The CTL dissociates from the target cell and is able to then kill further target cells.

Fig 14-7

1) CTL cytoplasmic granules contain perforin, which can form pores in the

target cell membrane.

2) These pores allow other toxic molecules released by the CTL to enter the target cell and induce it to undergo apoptosis. 1

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Natural Killer (NK) Cells

• Make up 5-10% of circulating lymphocytes

• Originate from lymphoid lineage

• First line of defense against viruses,

tumors and intracellular bacteria

• Main source of IFN-γ early during infection

• This IFN-γ can direct Th responses towards Th1-type

• Stimulated by IFN-α/IFN-β and IL-12

NK Cells and T cells

• Express unique markers:– CD2 (receptors for LFA-3)

– CD16 (FcγRIII)

– CD56 (adhesion molecule)

• Do not undergo maturation in the thymus

• Present in mice lacking thymus

• Lack CD3-TCR

• Do not show MHC-restriction

• Do not require activation

Killing by NK cells

• Similar to CTLs

• Presence of two types of receptors:

activating receptors and inhibitory receptor

• Activating receptors: NKR-P1 (C-type

lectin), CD2, FcγRIII, and NKp30, NKp44, NKp46

• Inhibitory receptor:

– C-type-lectin inhibitory receptors (CLIR):

CD94/NKG2

– Killer cell-inhibitory receptors (KIR)

Opposing Signal Model in NK cells (Activation VS Inhibitory)

Normal levels of MHC-1

Decreased levels of

MHC-1

Veto Power!!!!

Antibody-dependent cell-mediated cytotoxicity (ADCC)

• This mechanism is triggered when

antibody is bound to a target cell

• ADCC can be mediated by: NK cells,

macrophages, monocytes, neutrophils and eosinophils

• Killing is mediated by release of: lytic

enzymes, TNF-α, perforin and granzymes

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Experimental Assessment of Cell-Mediated Cytotoxicity

At least 3 ways:

a) Mixed lymphocyte reaction (MLR)

b) Cell-mediated lympholysis (CML)

c) Delayed type hypersensitivity (DTH)

DTH - Delayed-type hypersensitivity

- DTH is a second major form of cell-mediated immunity.

- As with humoral immunity and cytotoxic T cell responses, DTH is controlled by helper T cells.

- In DTH, the effector cell is non-antigen-specific: the macrophage.

- DTH responses occur to specific types of antigen: intracellular bacteria, viruses, and certain chemicals.

-A DTH response is basically an inflammatory responseinduced by T helper cells.

- Hallmark: delay in time and recruitment of Macrophages

Antigens that induce DTH

The DTH response has two phases - sensitization and

effector phases.

Sensitization phaseoccurs on first contact with

antigen. Helper T cells are activated but mediate no DTH

response.

Langerhans cells

Fig 14-15b

Effector phase- occurs after second exposure to the antigen. Peaks at 48

hr)

T cells specific for the antigen secrete cytokines (IFN-γγγγ, TNF-β) that recruit and activate macrophages and other inflammatory cells. These cells then

mediate the DTH response.

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DTH effector mechanisms

-IFN-gamma increases class II MHC expression on macrophagesand other cells

-IFN-gamma activates macrophages and causes them to releaseadditional inflammatory mediators

-TNF-beta mediates local tissue destruction and alters adhesion

molecules on local blood vessel endothelium to facilitateextravasation of other cells (eg neutrophils)

-IL-3 and GM-CSF enhance monocyte production by the bone

marrow.

-The chemokine MCP (macrophage chemotactic protein) recruits

monocytes to the site of the antigen

- The chemokine MIF (migration inhibition factor) MIP retains

macrophages at the site of the antigen

DTH effector mechanisms

-The macrophages that are recruited by the T cells can…

- Undergo the respiratory burst and produce oxygen radicals –

which kill bacteria

- Produce nitric oxide

- Phagocytose cellular debris

- Secrete cytokines - esp. TNF-alpha and IL-1 (endothelial cells)

- Continue to present antigen and to stimulate helper T cells – andthereby continue the reaction as long as antigen is present.

-As a result - a DTH reaction will generally cause localized tissue swelling 24 to 72 hours after it is initiated.

Chronic DTH reactions

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This low power photomicrograph shows numerous discrete, uniformly sized, round granulomas scattered throughout a lymph

node.They are composed of epithelioid cells which stand out pale against the darkly staining lymphocytes in which they are set. Giant

cells are not obvious. The capsule of the lymph node can be seen at the top, giving a clue to the size of the structures - probably 0.5 to

1.0 mm across. The disease process here is sarcoidosis, a chronic granulomatous disease of unknown etiology.

From: http://medweb.bham.ac.uk/http/depts/path/Teaching/FOUNDAT/CHRONINF/grancell.html

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Fig 14-17

Role of IFN-gamma in DTH