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Funzioni delle cellule NK

Le cellule NK sono una popolazione di linfociti


già pronta ad uccidere; hanno infatti granuli
citoplasmatici comprendenti perforina e
Granzyme A e B. La perforina è simile al C9 del
complemento; esiste in due forme: attiva
(idrofobica) e inattiva (idrofila). Essa polimerizza
formando pori acquosi sulla cellula da uccidere.
Le molecole più importanti sono granzyme A e B
che inducono apoptosi (morte programmata simil
suicidio) nella cellula stessa. La lisi della cellula
bersaglio sia essa tumore o infettata da virus
avviene grazie a 2 meccanismi: una lisi osmotica
dovuta ai pori, ma soprattutto per il fatto che
attraverso questi pori vengono introdotti nel
bersaglio granzyme A e B inducenti apoptosi, in
modi differenti:
─ A: causa grossolani tagli al DNA
─ B attiva le vie classiche dell'apoptosi (cascata
delle caspasi).

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© 2005 Elsevier
Le cellule NK e i linfociti T hanno recettori complementari
Activating and inhibitory receptors
of NK cells.
A. Activating receptors of NK cells
recognize ligands on target cells and
activate protein tyrosine kinase
(PTK), whose activity is inhibited by
inhibitory receptors that recognize
class I MHC molecules and activate
protein tyrosine phosphatase (PTP).
NK cells do not efficiently kill class I
MHC-expressing healthy cells.

B. If a virus infection or other stress


inhibits class I MHC expression on
infected cells, and induces expression
of additional activating ligands, the
NK cell inhibitory receptor is not
engaged and the activating receptor
functions unopposed to trigger
responses of NK cells, such as killing
of target cells and cytokine secretion.
Il CD16: un recettore attivatorio che promuove ADCC

Le cellule NK esprimono il CD16, un recettore per la regione Fc delle IgG (v. Struttura
degli anticorpi, più avanti), e possono utilizzare questo recettore per mediare un altro tipo
di lisi cellulare che non presenta restrizione MHC. La citotossicità cellulo-mediata
anticorpo-dipendente (Ab-Dependent Cell-mediated Cytotoxicity, ADCC) dipende dalla
presenza di Ac che riconoscono una cellula bersaglio (la sua specificità è pertanto dovuta
alla specificità dell'Ac). In seguito al legame con il suo Ag, la regione Fc dell'Ac viene
esposta e si lega poi al suo recettore sulla cellula NK per formare un ponte molecolare.
Una volta formato il ponte, alla cellula bersaglio viene trasmesso un segnale litico ancora
non del tutto compreso, il quale ne determina la morte.
EFFECTOR CELLS OF INNATE IMMUNITY
FcR Affinity for immunoglobulin Cell distribution Function
FcγRI (CD64) High (Kd ∼ 10-9 M); binds IgG1 and IgG3, Macrophages, neutrophils; Phagocytosis; activation of
can bind monomeric IgG also eosinophils phagocytes
FcγRIIA (CD32) Low (Kd > 10-7 M) Macrophages, neutrophils; Phagocytosis; cell
eosinophils, platelets activation (inefficient)
FcγRIIB (CD32) Low (Kd > 10-7 M) B lymphocytes Feedback inhibition of B
cells
FcγRIIIA Low (Kd > 10-6 M) NK cells Antibody-dependent cell-
(CD16) mediated cytotoxicity
FcγRIIIB Low (Kd > 10-6 M); GPI-linked protein Neutrophils, other cells Phagocytosis (inefficient)
(CD16)
FcεRI High (Kd > 10-10 M); binds monomeric IgE Mast cells, basophils, Cell activation
eosinophils (degranulation)
FcεRII (CD23) Low (Kd > 10-7 M) B lymphocytes, eosinophils, Unknown
Langerhans cells
FcαR (CD89) Low (Kd > 10-6 M) Neutrophils, eosinophils, Cell activation?
monocytes
LE CELLULE NK POSSONO MEDIARE LA
CITOTOSSICITA’ ANTICORPO DIPENDENTE (ADCC)
Lez 8
• Adaptive (specific) immunity
The two arms of the Immune Response:

APC
Homing and trafficking of DC during their maturation

CCR7-/CCR5+

CCR7+/CCR5-
mature DC

Molecules expressed by matured DC


PPRs
Switch CK-R durante maturazione DC

Maturazione delle cellule dendritiche

NF-kB

PPRs
Filmato: Dendritic cell migration
Janeway
Also residing in Bone Marrow:
CD34+ and stem cell antigen-1+ (Sca-1+)
Hematopoietic cytokines
Are produced by stromal
Cells and macrophages in
the bone marrow

CSFs Abs producing B cells


Promote maturation and
Some memory T cells
diffentiation of precursors
cells

Hematopoiesis. The development of the different lineages of blood cells is depicted in this "hematopoietic tree
Timus: is derived from invagination of the ectoderm in the developing neck and chest of the embryo

Timus: bilobates organ


D-George syndrome: In the anterior mediastin
(spazio della cavità toracica situato nella
T cells deficiency, because mutation in parte mediana, tra i due polmoni, e
gene endoding a transcription factor delimitato in avanti dallo sterno,
required for Thymus development in basso dal diaframma, posteriormente
dalla colonna vertebrale, mentre superiormente
è in diretta comunicazione con lo spazio
viscerale del collo. )

T cells rich zone

Most immature T cells Setti fibrosi

Mostly mature T cells


Efferent lymphatic vessel
drain into mediastinal lymphnodes

Epithelials cells:
remnatns of degenerating
epithelial cells

Morphology of the thymus. A. Light micrograph of a lobe of the thymus showing the cortex and medulla. The blue-stained cells are
developing T cells called thymocytes. B. Schematic diagram of the thymus illustrating a portion of a lobe divided into multiple lobules
by fibrous trabeculae.
Il timocita che giunge nel timo non esprime né CD4 né CD8 (doppio negativo). Nella corticale del timo
da doppio negativo diventa doppio positivo, ovvero esprime sia CD4 che CD8. Successivamente nella
midollare esprimerà o esclusivamente CD4 o esclusivamente CD8 e quindi sarà o CD4 positivo o CD8
positivo.

CD4+ T cell: MHC


classe II

CD8+ T cell: MHC


classe I

Selection processes in the thymus. A. Positive selection. If the thymocyte TCR engages in a low-affinity interaction with a self MHC molecule on a
thymic epithelial cell, it is rescued from programmed cell death and continues to mature. B. Lack of positive selection. If the thymocyte TCR does not engage in
any interactions with peptide-MHC molecule complexes on thymic epithelial cells, it will die by a default pathway of programmed cell death. C. Negative
selection. If the thymocyte TCR binds peptide-MHC complexes on a thymic antigen-presenting cell with high affinity or avidity, it is induced to undergo apoptotic
cell death.
Lymphatic vessel merge
Into afferent lymph vessels
that drain into the subcapsular
Pathways of T lymphocyte recirculation
Sinus of lymph nodes. DC leave
the lymph and enter the

paracortex

Common portal entry:


Skin,
lung,
gastrointestinal tracts

(Large lymphatic vessel)

Arterial circulation
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Skin, epithelia and parenchymal organs contain numerous lymphatic capillaries that absorb
and drain interstitial fluid from these sites

Centro di raccolta della linfa che


proviene dagli arti inferiori a dal
tronco

The lymphatic system. The major lymphatic vessels and collections of lymph nodes are illustrated. Antigens are captured from a site
of infection, and the draining lymph node to which these antigens are transported and where the immune response is initiated.
CCL19
CCL21

CCR7+
CXCR5
CXCL13

HEV

hilum
CCR7 (CCL19, CCL21)

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Also residing in Bone Marrow:
CD34+ and stem cell antigen-1+ (Sca-1+)
Hematopoietic cytokines
Are produced by stromal
Cells and macrophages in
the bone marrow

CSFs Abs producing B cells


Promote maturation and
Some memory T cells
diffentiation of precursors
cells

Figure 3-6 Hematopoiesis. The development of the different lineages of blood cells is depicted in this "hematopoietic tree." The roles of cytokines in hematopoiesis are
illustrated in Chapter 12, Figure 12-15. CFU, colony-forming unit.
CXCL13

CCL19, CCL21

Segregation of B cells and T cells in a lymph node. A. The schematic diagram illustrates the path by which naive T and B lymphocytes
migrate to different areas of a lymph node. The lymphocytes enter through an artery and reach an HEV, shown in cross-section, from
where naive lymphocytes are drawn to different areas of the node by chemokines that are produced in these areas and bind selectively
to either cell type. Also shown is the migration of dendritic cells, which pick up antigens from the sites of antigen entry, enter through
afferent lymphatic vessels, and migrate to the T cell-rich areas of the node. B. In this section of a lymph node, the B lymphocytes,
located in the follicles, are stained green; the T cells, in the parafollicular cortex, are red. The anatomic segregation of T and B cells is
also seen in the spleen
Morphology of a lymph node. A. Schematic
diagram of a lymph node illustrating the T cell-
rich and B cell-rich zones and the routes of
entry of lymphocytes and antigen (shown
captured by a dendritic cell). B. Schematic of
the microanatomy of a lymph node depicting
the route of lymph drainage from the
subcapsular sinus, through fibroreticular cell
conduits, to the perivenular channel around the
HEV. C. Light micrograph of a lymph node
illustrating the T cell and B cell zones.
Migration of naive and effector T lymphocytes. A. Naive T lymphocytes home to lymph nodes as a result of L-selectin binding to its
ligand on HEVs, which are present only in lymph nodes, and as a result of binding chemokines (CCL19 and CCL21) displayed on the
surface of the HEV. Activated T lymphocytes, including effector cells, home to sites of infection in peripheral tissues, and this
migration is mediated by E- and P-selectins and integrins, and chemokines that are produced at sites of infection. Additional
chemokines and chemokine receptors, besides the ones shown, are involved in effector/memory T cell migration. B. The adhesion
molecules, chemokines, and chemokine receptors involved in naive and effector/memory T cell migration are described.
Routes of antigen entry. Microbial antigens commonly enter through the skin and gastrointestinal and respiratory
tracts, where they are captured by dendritic cells and transported to regional lymph nodes. Antigens that enter the
blood stream are captured by antigen-presenting cells in the spleen.
Speen. A major site of immune responses to blood-borne antigens

Single spenic artery White pulp promotes


adaptive immune response
to blood antigens
DC deliver antigens
In the marginal sinus

Several smaller branches


CXCR5 of the central artery cross the
CXCL13 perierteriolar lymphoid sheat
and drain into a vascular sinus
(called marginal sinus: contains
CCR7: Marginal zone B cells and
CCL19, specialized macrophages).
CCL21

draining into splenic vein

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Corpuscolo di Malpighi (polpa bianca)

Morphology of the spleen. A. Schematic diagram


of the spleen illustrating T cell and B cell zones,
which make up the white pulp. B. Photomicrograph
of a section of human spleen showing a trabecular
artery with adjacent periarteriolar lymphoid sheath
and a lymphoid follicle with a germinal center.
Surrounding these areas is the red pulp, rich in
vascular sinusoids. C. Immunohistochemical
demonstration of T cell and B cell zones in the
spleen, shown in a cross-section of the region
around an arteriole. T cells in the periarteriolar
lymphoid sheath are stained red, and B cells in the
follicle are stained green.
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Role of dendritic cells in antigen capture and presentation. Immature dendritic cells in the skin (Langerhans cells) or dermis
(dermal DCs) capture antigens that enter through the epidermis and transport the antigens to regional lymph nodes. During
this migration, the dendritic cells mature and become efficient antigen-presenting cells. The table summarizes some of the
changes during dendritic cell maturation that are important in the functions of these cells.
I componenti del tessuto MALT si possono suddividere in 5 gruppi:
(Linfoma MALT da H. Pylori)
GALT (gut-associated lymphoid tissue), tessuto linfoide associato all'intestino, tra
cui vi sono le placche di Peyer

BALT (bronchial-associated lymphoid tissue), tessuto linfoide associato all'area


bronchiale

NALT (nose-associated lymphoid tissue), tessuto linfoide associato al naso

VALT (vascular-associated lymphoid tissue), tessuto linfoide associato ai vasi


sanguigni, che rappresenta una nuova componente del MALT ma di cui ancora non
si conosce il ruolo nella risposta immunitaria
::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::
CALT (conjunctiva-associated lymphoid tissue in the human eye), tessuto linfoide
associato alla congiuntiva

SALT (skin-associated lymphoid tissue), tessuto linfoide associato alla pelle

FALT (Faringeal associated Lymphoid tissue) associato alla faringe

ASSICURA RISPOSTA IMMUNITARIA COMPLETA, B e T


(internalizzano gli antigeni provenienti dalla digestione
e li forniscono ad APC)

aggregations of lymphoid tissue that are usually found in


the lowest portion of the small intestine ileum in humans

B-cells and memory cells are stimulated upon encountering antigen in


Peyer's patches. These cells then pass to the mesenteric lymph nodes
where the immune response is amplified.

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Mainly CD4+ T cells
Microfold cells
(M: membranous)

Mainly CD8+ T cells


B cells rich area

L-selectin,
a4b7 T lymphocytes

The mucosal immune system. A. Schematic diagram of the cellular components of the mucosal immune system in the intestine. B.
Photomicrograph of mucosal lymphoid tissue in the human intestine. Similar aggregates of lymphoid tissue are found throughout the
gastrointestinal tract and the respiratory tract.
Migration of naïve and effector T cells
Da qui
Homing and trafficking of DC during their maturation

CCR7-/CCR5+

CCR7+/CCR5-

Molecules expressed by matured DC


ADATTATIVA : recettori distribuiti clonalmente

Precursore
Riarrangiamento
Genico

Antigene

Clone
ADATTATIVA : recettori distribuiti clonalmente

Precursore
Riarrangiamento
Genico

Antigene

Clone

Encounter with THE antigen generates effector T cells


and long-lived memory T cells.
The central role of CD4+ T lymphocytes
Different types of antigen-presenting cells
La restrizione MHC (Major Histocompatibility Antigen)

I linfociti T “vedono” A 1° segnale A


l’antigene
solo se presentato
all’interno TCR Ag MHC
di MHC “self” LINFOCITA Cellula che
T presenta
Vaccini con DC autologhe

I linfociti vengono attivati


soltanto dal riconoscimento
di un antigene estraneo A B
NON-SELF
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The MHC molecules of an individual do not discriminate between foreign peptides
(e.g., those derived from microbial proteins) and peptides derived from the proteins of that individual (self antigens ).

The antigen receptors of T


cells recognize both the
antigenic peptide and the
The binding of peptides to MHC molecules, with the
MHC molecules is a peptide being responsible
noncovalent for the fine specificity of
interaction mediated by antigen recognition and
residues both in the the MHC residues
peptides and in accounting for the MHC
the clefts of the MHC
restriction of the T cells.
molecules.

8-11 residues

Antigen competition for T cells. A T cell recognizes a peptide presented by one MHC molecule. An excess of a different peptide that binds to the
same MHC molecule competitively inhibits presentation of the peptide that the T cell recognizes. APC, antigen-presenting cell.
T cell recognition of a peptide-MHC complex. This schematic illustration shows an MHC molecule binding and displaying a
peptide and a T cell receptor recognizing two polymorphic residues of the MHC molecule and one residue of the peptide.
MHC genes control graft rejection and immune responses. The two strains of mice shown are identical except for their MHC
alleles (referred to as a and b). These strains reject skin grafts from each other (A) and respond differently to immunization
with a model protein antigen (usually a simple polypeptide) (B).
HLA: human leukocyte antigen (chromosom 6)

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Protein antigens present in acidic vesicular compartments of APCs generate class
II-associated peptides, whereas antigens present in the cytosol generate class I-
associated peptides.

Pathways of antigen processing and presentation. In the class II MHC pathway (top panel), extracellular protein antigens are endocytosed into
vesicles, where the antigens are processed and the peptides bind to class II MHC molecules. In the class I MHC pathway (bottom panel), protein
antigens in the cytosol are processed by proteasomes, and peptides are transported into the ER, where they bind to class I MHC molecules.
Comparative Features of Class II and Class I MHC Pathways of Antigen Processing and Presentation

Feature Class II MHC Pathway Class I MHC pathway


Composition of stable peptide- Polymorphic α and β chains, Polymorphic α chain, β2-microglobulin,
MHC complex
Types of APCs Dendritic cells, mononuclear phagocytes, B All nucleated cells
lymphocytes; endothelial cells, thymic
epithelium
Responsive T cells CD4+ T cells CD8+ T cells
Source of protein antigens Endosomal/lysosomal proteins (mostly Cytosolic proteins (mostly synthesized in
internalized from extracellular environment) the cell; may enter cytosol from
phagosomes)
Enzymes responsible for peptide Endosomal and lysosomal proteases (e.g., Cytosolic proteasome
generation cathepsins)
Site of peptide loading of MHC Specialized vesicular compartment Endoplasmic reticulum
Molecules involved in transport of Chaperones in ER; invariant chain in ER, Chaperones, TAP in ER
peptides and loading of MHC Golgi and MIIC/CIIV; DM
molecules

Abbreviations: APC, antigen-presenting cell; CIIV, class II vesicle; ER, endoplasmic reticulum; MHC, major histocompatibility
complex; MIIC, MHC class II compartment; TAP, transporter associated with antigen processing
Class II MHC
Class I MHC
Pathophysiological significance of Class I-associated
antigen presentation
Riconoscere l’antigene con il TCR specifico non basta!

E’ necessario un 2° segnale dato dalla cellula che presenta l’antigene


IMPORTANCE OF CO-STIMULATION

1° segnale 2° segnale

B
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I tumori sperimentali murini esprimono
antigeni immunogenici

Prehn 1950
Mechanisms of evasion from immune surveillance

•Tumor antigens are poorly immunogenic


•Lack or loss of immunogenic peptides
•Loss of MHC molecules
•Lack of co-stimulatory molecules
•Production of immune-suppressive factors
(IL-10, TGFb, VEGF ……)

•Low frequency of tumor specific effectors


•Alteration of effector mechanisms
•Activation of suppressor T cells