Aktivasi Sel t Limfosit

5/21/2018 Aktivasi Sel t Limfosit

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AKTIVASI SEL T LIMFOSIT

Dyah Ratna Budiani

Bag. Biomedik/ Bag. Patologi Anatomi

Fakultas KedokteranUniversitas Sebelas Maret


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Antigen recognition


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Presentasi antigen by MHC class II or class I


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T receptor & accessory molecules


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EXPERIMENTAL MODELS USED TO STUDY T-

CELL ACTIVATION

Parameter of T cell activated :

(a) early signal transduction events, such as protein

tyrosine phosphorylation or an increase in

cytoplasmic free calcium ([Ca2+]i), that do not

necessarily lead to a cellular response;(b) expression of new cell surface activation antigens,

Including the a chain (CD25) of the IL-2 receptor (IL-

2R), the transferrin receptor, class II MHC molecules

on human T cells, and CD69, a molecule with as yet

unknown function;

(c) production of lymphokines, such as IL-2 or IL-4;

(d) cell proliferation; and

(e) cytolytic activity.


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Requirements for the Initiation of T-

Cell Activation

Aktivasi sel T diinisiasi oleh adanya : interaksi antar sel . Spesifik antigen

dengan TCR mengawali interaksi antara sel T dan APC.

Antigenic peptides bound to MHC molecules on APCs are recognized by T

cells bearing antigen-specific TCRs. Disamping itu ikatan antara ke dua

sel ini juga diperkuat dengan adanya ikatan beberapa molekul lain (gambar1).

The TCRand other cell surface moleculescontribute to the initiation of T-

cell activation by inducing signal transductionevents and by contributing

to the overall avidity of the T cellAPC interaction.

Considerable evidence has accumulated to suggest that at least one molecule,

a co-stimulatory receptor, must initiate signal transduction events distinct

from the TCR in order to initiate IL-2 secretion and induce a proliferative

response in naive T cells.


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T CELL

APC or

TARGET CELL

T CELL TERAKTIVASI SEKRESI IL-2 ( T CELL Growth

factor)

EKSPRESI IL-2 RECEPTOR

PROLIFERASI & DIFERENSIASI SEL T


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Event Example

Cellcell interaction T cellAPC

CTLTarget Cell

Receptor-ligand binding TCR-Antigen/MHC

Transmembrane signal transduction Activation of Lck

Generation of second messengers 1,4,5-IP3 and DG

Second messenger effects Ca2+ mobilization

Protein kinase C

activation Biochemical pathways Phosphatidylinositol

pathway

Ras pathway

Cellular events MTOC reorganization

Secretion of cytolyticgranules

Early gene activation c-myc, c-fos

Intermediate gene activation Lymphokines,lymphokine receptors,nutrient receptors

Late gene activation Genes involved in cellproliferation, 4F2,VLA-2

MAJOR EVENTS INVOLVED IN T CELL ACTIVATION


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T CELL ANTIGEN RECEPTOR


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Figure 3. Interaksi antara

sel T dan APC yang

berujung pada produksi IL-2.Interaksi seguensial antara

TCR dengan peptida

antigen-MHC Complex,

memacu ekspresi protein

CD40L pada sel T yang

berinteraksi dengan CD40pada permukaan APC. Hal

ini menginduksi ekspresi

molekul B7 pada APC yang

dapat menstimulasi CD28

yg mrpkn co-stimulatory

receptor pd sel T. Keduasignal ini bersama-sanma

menginduksi ekspresi gen

IL-2.

Stimulasi produksi IL-2


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The role of IL-2 in REGULATION OF T-

CELL PROLIFERATION

Antigen-activated T cells that produce IL-2 can :

(a) promote their own clonal expansion,

(b) promote the proliferation of other T cells that areactivated by the same or a related specific antigenbut can not produce IL-2 (i.e., CD8+ cells),

(c) promote the expansion of previously stimulatedcells that express low levels of high-affinity IL-2Rs(i.e., memory T cells), and

(d) promote the proliferation of non-T cells that express

IL-2Rs (i.e., B cells or NK cells). In addition to itsgrowth-promoting effects on various cellpopulations, IL-2 can influence the development ofvarious differentiated functional activities.


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Stimulation of the TCR induces naive T cells to progress fromthe G0 to the G1 stage of the cell cycle and to express high-affinity IL-2s

The function of IL-2 is to promotefurther progression through

the cell cycle. The ability of IL-2 to induce cell cycleprogression, from G1 through S, G2, and M, depends on thebinding of IL-2 to its high-affinity receptor.

Although IL-2 may not be the only lymphokine that can induceT-cell proliferation, the importance of IL-2 in promoting suchcell cycle progression in peripheral T cells is underscored bythe decreased proliferative response to mitogenic and antigenstimulation of T cells from mice in which the IL-2 has beendisrupted by homologous recombination. Hence, the binding ofIL-2 to its receptor and the ensuing signal transduction eventsplay central roles in most immune responses.

The role of IL-2 in REGULATION OF T-

CELL PROLIFERATION


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IL-2 Reseptor

Setidaknya ada 3 jenis rantai IL-2 reseptor

1. Rantai CD25, the IL-2R chain, is a 55-kD integralmembrane glycoprotein that has an affinity constant (KD) of10-8 M. This low-affinity form of the IL-2R comprises the mostabundant form of the IL-2R expressed on activated T cells and

human T-cell leukemia virustransformed lines.

2. Rantai : a 70-kD glycoprotein, binds IL-2 with intermediate affinity

(KD of approximately 10-9 M) when it is expressed on T cells.

3. Rantai : The IL-2R chain is a 64-kD integral membrane protein.The and chains of the IL-2R are members of a family of cytokinereceptors that have related structural features in their extracellulardomains

The high-affinity IL-2binding site appears to result from the

combined characteristics of the b and g chains.


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Model Reseptor IL-2


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SIGNAL TRANSDUCTION BY THE T-CELL ANTIGEN RECEPTOR

Src PTKs Involved in TCR Signal Transduction

Lck and Fyn are the major Src family PTKs expressed in T cells. Both have

been implicated in interactions with ITAMs and in TCR signal transduction.Prior to reviewing the specific role of each of these kinases, the overallcommon structural features (Fig. 5).

The Src kinases vary from approximately 50 to 60 kDa172. At the N-terminus of

each of these kinases, at position 2, is a glycine residue that is

myristoylated. This allows for membrane attachment. Some of the Src

kinases, including Lck, are also palmitoylated at one or two cysteineresidues contained within the first ten residues, and this modification may

be dynamically regulated. This further facilitates membrane localization,

particularly the plasma membrane. Within the N-terminal, 40 to 70 residues

are also the most distinguishing sequences among this family that probably

play important roles in the unique functions and interactions of each of

these kinases. The unique region is followed by the Src homology 3 (SH3)domain, which consists of approximately 60 residues. The SH3 domain is

involved in directing proteinprotein interactions by binding in a sequence

specific context to residues contained in proline-rich regions. The SH3

domain is followed by a 100-amino acid structural domain, the SH2 domain.

The SH2 domain also is involved in proteinprotein interactions by binding

to phosphorylated tyrosine residues contained in a particular sequence-s ecific context.


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Inhibitors used to study T-cell activation

Inhibitor Target

Neomycin Phosphatidylinositol turnover

Lithium Inositol phosphate phosphatase

H7 Protein kinase C

Sphingosine Protein kinase C

Staurosporine Protein kinase C

Genestein Tyrosine kinase

Herbimycin A Tyrosine kinase

Tyrphostin Tyrosine kinase

Vanadate Tyrosine phosphatase

Phenylarsine oxide Tyrosine phosphatase (?)

EDTA Ca2+ and Mg2+

EGTA Ca2+ Dimethylamiloride Na+/H+ antiporter

Glucocorticoids Glucocorticoid receptor; diverse effects

Cyclosporin A Calcineurin

FK506 Calcineurin

Rapamycin mTor

Wortmannin Phosphatidylinositol 3-kinase LY294002 Phosphatidylinositol 3-kinase


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THE REGULATION OF T-CELL

PROLIFERATIONOther Mechanisms Regulating T-Cell Growth

IL-4 and IL-15 are the most likely to

function as T-cell growth factors in the

absence of IL-2.

Aktivasi Sel t Limfosit

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