AKTIVASI SEL T LIMFOSIT

Dyah Ratna Budiani

Bag. Biomedik/ Bag. Patologi Anatomi
Fakultas Kedokteran
Universitas Sebelas Maret
Antigen recognition
Presentasi antigen by MHC class II or class I
T receptor & accessory molecules

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.
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 (gambar
1).
The TCR and other cell surface molecules contribute to the initiation of T-
cell activation by inducing signal transduction events 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.

T CELL
APC or
TARGET CELL
T CELL TERAKTIVASI SEKRESI IL-2 ( T CELL Growth
factor)
EKSPRESI IL-2 RECEPTOR
PROLIFERASI & DIFERENSIASI SEL T
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 cytolytic
granules
Early gene activation c-myc, c-fos
Intermediate gene activation Lymphokines,
lymphokine receptors,
nutrient receptors
Late gene activation Genes involved in cell
proliferation, 4F2,VLA-2
MAJOR EVENTS INVOLVED IN T CELL ACTIVATION
T CELL ANTIGEN RECEPTOR
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 CD40
pada permukaan APC. Hal
ini menginduksi ekspresi
molekul B7 pada APC yang
dapat menstimulasi CD28
yg mrpkn co-stimulatory
receptor pd sel T. Kedua
signal ini bersama-sanma
menginduksi ekspresi gen
IL-2.
Stimulasi produksi IL-2
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 are
activated by the same or a related specific antigen
but can not produce IL-2 (i.e., CD8+ cells),
(c) promote the expansion of previously stimulated
cells 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 its
growth-promoting effects on various cell
populations, IL-2 can influence the development of
various differentiated functional activities.
Stimulation of the TCR induces naive T cells to progress from
the G0 to the G1 stage of the cell cycle and to express high-
affinity IL-2s
The function of IL-2 is to promote further progression through
the cell cycle. The ability of IL-2 to induce cell cycle
progression, from G1 through S, G2, and M, depends on the
binding of IL-2 to its high-affinity receptor.
Although IL-2 may not be the only lymphokine that can induce
T-cell proliferation, the importance of IL-2 in promoting such
cell cycle progression in peripheral T cells is underscored by
the decreased proliferative response to mitogenic and antigen
stimulation of T cells from mice in which the IL-2 has been
disrupted by homologous recombination. Hence, the binding of
IL-2 to its receptor and the ensuing signal transduction events
play central roles in most immune responses.
The role of IL-2 in REGULATION OF T-
CELL PROLIFERATION
IL-2 Reseptor
Setidaknya ada 3 jenis rantai IL-2 reseptor

1. Rantai CD25, the IL-2R chain, is a 55-kD integral
membrane glycoprotein that has an affinity constant (KD) of
10-8 M. This low-affinity form of the IL-2R comprises the most
abundant 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 cytokine
receptors that have related structural features in their extracellular
domains
The high-affinity IL-2binding site appears to result from the
combined characteristics of the , b, and g chains.

Model Reseptor IL-2

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 overall
common 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 cysteine
residues 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-
specific context.
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
THE REGULATION OF T-CELL
PROLIFERATION
Other 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.