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Downloaded from: StudentConsult (on 8 November 2008 07:57 PM)© 2005 Elsevier

L-4 is the major stimulus for the production of IgE antibodies and for the development of TH2 cells from naive CD4+ helper T cells. IL-4 is the signature cytokine of the TH2 subset and functions as both an inducer and an effector cytokine of these cells.

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• IFN-γ is the principal macrophage-activating cytokine and serves critical functions in innate immunity and in adaptive cell-mediated immunity against intracellular microbes. IFN-γ isalso called immune, or type II, IFN. Although it has some antiviral activity, it is not a potentantiviral cytokine, and it functions mainly as an activator of effector cells of the immune system.

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A. CD4+ TH1 cells and CD8+ T cells recognize class II MHC-associated or class I MHC-associated peptide antigens of phagocytosed microbes, respectively, and produce cytokines that activate the phagocytes to kill the microbes and stimulate inflammation.

B. CD8+ CTLs recognize class I MHC-associated peptide antigens of microbes residing in the cytoplasm of infected cells and kill the cells.

Types of T cellTypes of T cell--mediated immune reactionsmediated immune reactions

Le cellule dendritiche sono in grado di presentare Ag vescicolari endocitati attraverso il pathway di classe I. Le stesse APC “cross-presentanti” possono presentare presentare Ag associati a classe II a linfociti T CD4+.


CrossCross--presentationpresentation di antigeni a linfociti T CD8+di antigeni a linfociti T CD8+

Cellule infettate con microrganismi intracellulari, come i virus, sono ingeriti dalle cellule dendritiche

Gli Ag micribici sono processai e presentati in associazione a molecole MHC di classe I ai linfociti T CD8+.

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ImmunitImmunitàà cellulocellulo--mediatamediata verso verso L. L. monocytogenesmonocytogenes

TrasferimentoImmunità

Linfociti T

Siero

In un saggio in vitro per testarel’immunità cellulo-mediata, ilpatogeno è stato eliminato damacrofagi attivati e non da linfocitiT(C).

L’immunità verso L. monocytogenesè misurata dall’inibizione dellacrescita batterica nella milza dianimali inoculati con una dose notadi batteri vivi a cui è stata “trasferital’immunità inoculandolo con LINFOCITI T o SIERO prelevati daun topo singenico precedentementeimmunizzato con bassa dose di L. monocytogenes

Saggio in vitro


• The induction and effector phases of cell-mediated immunity. Induction of response: CD4+ T cells and CD8+ T cells recognize peptides that are derived from protein antigens and presented by professional antigen-presenting cells in peripheral lymphoid organs. The T lymphocytes are stimulated to proliferate and differentiate, and effector cells enter the circulation. Migration of effector T cells and other leukocytes to the site of antigen: Effector T cells and other leukocytes migrate through blood vessels in peripheral tissues by binding to endothelial cells that have been activated by cytokines produced in response to infection in these tissues. Effector functions of T cells: Effector T cells recognize the antigen in the tissues and respond by secreting cytokines that activate phagocytes to eradicate the infection. CTLs also migrate to tissues and kill infected cells

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Risposta Effettrice dei linfociti T CD4e sottopopolazioni TH1 e TH2

• Il sistema immunitario risponde in maniera diversa a microrganismi diversi:

• Batteri extracellulari sono inglobati dai fagociti e se sono in grado di resistere all’uccisone intracellulare, la risposta acquisita porta all’attivazione dei fagociti e alla loro conseguente eliminazione.

• Nel caso di elminti di dimensioni troppo grandi per essere fagocitati la risposta immunitaria è dominata dalla produzione di anticorpi IgEe dall’attivazione degli eosinofili

• In entrambe i casi è coinvolta la risposta T helper CD4+ ma i meccanismi effettori sono diversi

I linfociti T helper CD4+ sono una popolazione eterogeneaPossono differenziarsi in sottopopolazioni di cellule effettrici che

producono uno spettro di citochine diverse, dotate di differentifunzioni: TH1 TH2


Properties of TH1 and TH2 subsets of CD4+ helper T cells. Naive CD4+ T cellsmay differentiate into distinct subsets, such as TH1 and TH2 cells, in response toantigen, costimulators, and cytokines. The table lists the major differences betweenthese two subsets.

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Development of TH1 and TH2 subsets. Cytokines produced in the innate immune response to microbes or early in adaptive immune responses influence the differentiation of naive CD4+ T cells into TH1 or TH2 cells. IL-12, made by activated macrophages and dendritic cells, induces TH1 cell development through a STAT4-dependent pathway. IL-4, which may be produced mainly by T cells themselves, favors induction of TH2 cells through a STAT6-dependent pathway. The transcription factor T-bet, produced in response to IFN-γ, is essential for TH1 responses, and GATA-3 is critical for TH2 differentiation. Other cytokines that may influence helper T cell differentiation are not shown.


• Role of IL-12 and IFN-γ in TH1 differentiation and cell-mediated immunity.Antigen-presenting cells secrete IL-12 in response to microbial products such aslipopolysaccharide (LPS), IFN-γ produced by NK cells and T cells, and CD40 engagement by T cell CD40L. IL-12 stimulates the differentiation of CD4+ helper T cells to TH1 effectors, which produce IFN-γ. IFN-γ then activates macrophages to killphagocytosed microbes (and to secrete more IL-12).

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Effector functions of TH1 cells. CD4+ T cells that differentiate into TH1 cells secrete IFN-γ, lymphotoxin (LT) and TNF, and IL-2. IFN-γ acts on macrophages to increasephagocytosis and killing of microbes in phagolysosomes and on B lymphocytes tostimulate production of IgG antibodies that opsonize microbes for phagocytosis. LT and TNF activate neutrophils and stimulate inflammation. IL-2 is the autocrine growthfactor made by this subset of T cells (not shown).


• Migration and retention of effector and memory T cells at sites of infection.Previously activated effector and memory T cells, but not naive cells, migrate through endothelium that is activated by cytokines (e.g., TNF) produced at a site of infection. In extravascular tissue, the T cells that specifically recognize antigen are activatedand retained, whereas T cells that do not encounter the antigen for which they are specific return to the circulation, largely through lymphatic vessels (not shown).

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• Activation and functions of macrophages in cell-mediated immunity. In cell-mediatedimmunity, macrophages are activated by CD40L-CD40 interactions and by IFN-γ and performseveral functions that kill microbes, stimulate inflammation, and enhance the antigen-presentingcapacity of the cells. Macrophages are also activated during innate immune reactions and performthe same functions


Delayed-type hypersensitivity reaction. Infection or immunization (vaccination) sensitizes an individual, and subsequent challenge with an antigen from the infectious agent elicits a DTH reaction. The reaction is manifested by induration with redness and swelling at the site of the challenge, which is undetectable at ∼4 hours and peaks at ∼48 hours.

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Morphology of a DTH reaction. Histopathologic examination of the reaction in skin, (previous slide) shows perivascular mononuclear cell infiltrates in the dermis (A). At higher magnification, the infiltrate is seen to consist of activated lymphocytes and macrophages surrounding small blood vessels in which the endothelial cells are also activated (B). (Courtesy of Dr. J. Faix, Department of Pathology, Stanford University School of Medicine, Palo Alto, California.)


Granulomatous inflammation. Histopathologic examination of a lymph node shows a granuloma with activatedmacrophages, multinucleated giant cells, and lymphocytes. In some granulomas, there may be a central area of necrosis. Immunohistochemical studies would identify the lymphocytes as T cells. This type of inflammation is a

chronic DTH reaction against persistent microbial and other antigens. (Courtesy of Dr. Henry Sanchez, Department of Pathology, University of California at San Francisco School of Medicine.)


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Effector functions of TH2 cells. CD4++ T cells that differentiate into TH2 cells secrete IL-4 and IL-5. IL-4 actson B cells to stimulate production of antibodies that bind to mast cells, such as IgE. IL-4 is also an autocrinegrowth and differentiation cytokine for TH2 cells. IL-5 activates eosinophils, a response that is important fordefense against helminthic infections. Cytokines from TH2 cells also inhibit macrophage activation and TH1-mediated reactions.


Steps in CTL-mediated lysis of target cells. A CTL recognizes the antigen-expressing target cell and isactivated. Activation results in the release of granule contents from the CTL, which delivers a lethal hit to the target. The CTL may detach and kill another target cell while the first target goes on to die. Note that formation of conjugates between a CTL and its target and activation of the CTL also require interactions between accessorymolecules (LFA-1, CD8) on the CTL and their specific ligands on the target cell; these are not shown.


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Note that in the CTL on the upper left, the granules have beenredistributed toward the target cell.

Immune Immune synapsesynapse betweenbetween CTLsCTLs and a target and a target cellcell..

A. Courtesy of Dr. P. Peters, Netherlands Cancer Institute, Amsterdam.

A. Electron micrograph of three CTLs from a cloned cell line specific forthe human MHC molecule HLA-A2 binding to an HLA-A2-expressing target cell (TC) within 1 minute after the CTLs and targets are m ixed.


B. Electron micrograph of the point of membrane contact between a CTL (left)and target cell (right). Two CTL granulesare near the synapse. Severalmitochondria are also visible.

Immune Immune synapsesynapse betweenbetween CTLsCTLs and a target and a target cellcell..

B. (Reprinted from Stinchcombe JC, G Bossi, S Booth, and GM Griffiths. The immunological synapse of CTL contains a secretory domain and membrane bridges. Immunity 8:751-761, 2001, © Cell Press, with permissionfrom Elsevier).

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