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Home , Cytotoxic T cell

Cell-mediated

Effector role – detect and eliminate cells infected with intracellular

Chapter 14 Two types:

1) Cytotoxic response: - Cytotoxic T cells (CTLs) to kill - Cell-Mediated Effector Responses infected and altered self-cells. - NK cells and

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

Naïve VS Effector cells The CTL response

Mediated by CD8+ cytotoxic T .

- CD8+ T cells that have not yet seen 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 CD2 (LFA-3) and LFA-1 (ICAM-1) - differentiate into effector CTL

4 NOTE: Memory CTL-Ps secrete enough IL-2 for 1 3 Expression of IL-2 own proliferation receptors occurs only after CTL-P (precursor ) 2 activation by antigen.

IL-2 from helper T cells 5 is usually required before CTL-P can proliferate and differentiate into effector CTL (though Ag-activated CTL-P can produce some IL-2).

FIG 14-1

1 Th cells provide IL-2 for proliferation of naïve CTL-Ps Killing by CTLs

• Lytic activity mediated by and • Fas-mediated

• Working together or independently

The two pathways of CTL-mediated killing: 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. 1 2

Fig 14-9

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 . 1

2

Fig 14-7

2 Natural Killer (NK) Cells • Make up 5-10% of circulating lymphocytes • Originate from lymphoid lineage • First line of defense against , 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 Killing by NK cells • Express unique markers: • Similar to CTLs – CD2 (receptors for LFA-3) • Presence of two types of receptors: – CD16 (Fc γRIII) activating receptors and inhibitory receptor – CD56 (adhesion molecule) • Activating receptors: NKR-P1 (C-type • Do not undergo maturation in the lectin), CD2, Fc γRIII, and NKp30, NKp44, • Present in mice lacking thymus NKp46 • Lack CD3-TCR • Inhibitory receptor: • Do not show MHC-restriction – C-type-lectin inhibitory receptors (CLIR): • Do not require activation CD94/NKG2 – Killer cell-inhibitory receptors (KIR)

Opposing Signal Model in NK cells (Activation VS Inhibitory) -dependent cell-

Normal levels of MHC-1 mediated (ADCC) Veto Power!!!! • This mechanism is triggered when antibody is bound to a target cell • ADCC can be mediated by: NK cells, macrophages, monocytes, neutrophils and eosinophils Decreased levels of MHC-1 • Killing is mediated by release of: lytic enzymes, TNF-α, perforin and granzymes

3 Experimental Assessment of

5 Cell-Mediated Cytotoxicity At least 3 ways: 3 2

a) Mixed reaction (MLR) b) Cell-mediated lympholysis (CML) c) Delayed type hypersensitivity (DTH) 1 4

Antigens that induce DTH DTH - Delayed-type hypersensitivity

- DTH is a second major form of cell-mediated immunity. - As with and cytotoxic T cell responses, DTH is controlled by helper T cells . - In DTH, the effector cell is non-antigen-specific: the . - DTH responses occur to specific types of antigen: intracellular bacteria, viruses, and certain chemicals. -A DTH response is basically an inflammatory response induced by T helper cells.

- Hallmark : delay in time and recruitment of Macrophages

Effector phase - occurs after second exposure to the antigen. Peaks at 48 The DTH response has two hr) phases - sensitization and effector phases. T cells specific for the antigen secrete (IFN-γγγ, TNF-β) that recruit and activate macrophages and other inflammatory cells. These cells then mediate the DTH response. Sensitization phase occurs on first contact with antigen. Helper T cells are activated but mediate no DTH response.

Langerhans cells Fig 14-15b

4 DTH effector mechanisms DTH effector mechanisms

-IFN-gamma increases class II MHC expression on macrophages -The macrophages that are recruited by the T cells can… and other cells

-IFN-gamma activates macrophages and causes them to release - Undergo the respiratory burst and produce oxygen radicals – additional inflammatory mediators which kill bacteria

-TNF-beta mediates local tissue destruction and alters adhesion - Produce nitric oxide molecules on local blood vessel endothelium to facilitate extravasation of other cells (eg neutrophils) - Phagocytose cellular debris

-IL-3 and GM-CSF enhance monocyte production by the bone - Secrete cytokines - esp. TNF-alpha and IL-1 (endothelial cells) marrow. - Continue to present antigen and to stimulate helper T cells – and -The chemokine MCP (macrophage chemotactic ) recruits thereby continue the reaction as long as antigen is present. monocytes to the site of the antigen

- The chemokine MIF (migration inhibition factor) MIP retains -As a result - a DTH reaction will generally cause localized tissue macrophages at the site of the antigen swelling 24 to 72 hours after it is initiated.

Chronic DTH reactions

3

2

1

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

5 Role of IFN-gamma in DTH

Fig 14-17

6