Download PowerPoint Presentation - Cell-Mediated Immunity

SEL-T, Sel- B dan MHC
• Dosen Imunologi
• Fakultas Farmasi Universitas
Pancasila
• Jakarta
Produksi sel darah dan leukosit
Cell-Mediated Immunity
• Adalah respon adaptiv imuniti yg di mediasi
oleh sel sistem imun spesifik:
– lymphocytes T Primer (T cells), juga sel macrophages dan
sel NK .
– Adalah immunitas yg dapat ditransfer dr satu organisme ke
organisme lain oleh sel limfoid, tetapi tdk dengan antibodi
serum.
• Sel-T adalah agen utama dari selular imuniti.y
Sel-T
• Adalah koordinator utama dan effektor
dari komponen selular imuniti
CD8+ cytotoxic T cell killing a tumor cell
• Terciri oleh perkembangannya di dalam
Thymus dan adanya T-cell receptor (TCR)
complex
Sel-T
• Ada dua tipe utama:
1. CD4+: Stimulate other immune cells.
2. CD8+ Cytotoxic T cells: Kill intracellularly-infected
cells.
• Ada dua tipe utama dari CD4+ T cells:
1. TH1: Inflammatory T cells -- Stimulate macrophages
and promote inflammatory responses.
2. TH2: Helper T cells -- Stimulate B-cells to produce
antibodies.
(A third type, TH3, has recently been shown to promote IgA production.)
Perkambangan sel-T dalam Thymus
Immature doublenegative
T cells (CD8-, CD4-)
Cortex
Medulla
Positive
selection/
negative
selection
CD8+ T cells
Immature double-positive
T cells (CD8+, CD4+)
CD4+ T cells
Mature T cells
Reseptor sel T
• Similar in structure to Immunoglobulins (similar to a single Fab fragment.
• Composed of two glycoprotein chains (/ or /). Most mature T cells
have TCRs composed of an  chain and a  chain (they are called / T
cells).
• Each chain has a constant region and a variable region, similar to an
antibody light chain.
• A TCR recognizes a small
Epitope-binding site
(8-13 aa) peptide epitope
 chain
 chain
displayed on MHC
Variable region
Constant region
Transmembrane region
TCR compared to Immunoglobulins
Similarities
• Both have specific Antigen-binding region created by the variable regions of two
polypeptide chains.
• Both display great potential for diversity via genetic recombination at the
genome level
Differences
• A TCR is monovalent (has one binding site). An Ig is bivalent (has two binding
sites).
• The TCR has no secreted form. It is always membrane-bound.
• The TCR does not recognize free antigen. Antigen must be presented to a T cell
on an MHC molecule
• There is no class switching for the TCR. Once made, the TCR does not change.
Epitope-binding site
 chain
 chain
Variable region
Constant region
Transmembrane region
T cell Receptor
Immunoglobulin
The T cell Receptor, cont.
• The TCR only recognizes specific peptide/MHC complexes expressed on the
surfaces of cells
• A TCR complex is composed of one heterodimeric TCR (ususally /), plus a
5-polypeptide CD3 complex which is involved in cell signalling for T cell
activation.
• Each TCR is produced through genetic recombination and recognizes one
small peptide epitope (about 8-13 amino acids).
• One T cell expresses only one specific type of TCR.
TCR: Antigen recognition
CD3 is the activation complex for the TCR
 
CD3
Binding of antigen/MHC to the TCR
stimulates CD3. CD3 then sends an
activation signal to the inside of the
T cell.
CD3
 
 

Cell signaling
TCR genetics: Similar to Ig genetics
(numbers of segments in book is off, just like for Ig genes)
C region (1)
J regions (61)
V regions (70-80)
 chain
V regions (52)
D1 (1)
J1 (6)
C1 (1)
 chain
D2 (1)
J2 (7)
C2 (1)
Responses to infection -- T cell component
Innate immunity
(0-4 hours)
Early induced
response
(4-96 hours)
Late adaptive
response
>96 hours)
Protective
immunity
Immunological
memory
Infection
Recognition by
pre-formed, nonspecific effectors
Removal of
infectious agent
Infection
Recruitment of
effector cells
Recognition and
activation of
effector cells
Infection
Transport of
antigen to
lymphoid organs
Recognition
by naïve
B and T cells
Infection
Recognition by
pre-formed, Ab
and T cells
Infection
Recognition by
memory B cells
and T cells
Removal of
infectious agent
Clonal expansion
and differentiation
to effector cells
Removal of
infectious agent
Removal of
infectious agent
Rapid expansion
and differentiation
to effector cells
Removal of
infectious agent
The adaptive immune response involving antigen-specific T cells and B cells is only one part of
the immune response and is required to protect against pathogens. A pathogen is by definition an
organism that can cause disease. In other words, a pathogen is an organism that can bypass
innate immunity and requires an adaptive immune response for clearance.
Generation of an adaptive immune response
• During an adaptive immune response,T cells which recognize
specific antigen(s) are selected for differentiation into armed
effector cells which undergo clonal expansion to produce a battery
of antigen-specific cells.
• Clonal expansion refers to the process by which antigen-specific T
cells or B cells are stimulated to reproduce clones of themselves to
increase the system’s repertoire of antigen-specific effectors.
• Activation of antigen-specific T cells (the initiation of the adaptive
response) occurs in the secondary lymph tissues (lymph nodes and
spleen).
• This activation depends upon antigen presentation by a
professional antigen presenting cell (APC) along with simultaneous
co-stimulation. (eg., B7 on the APC, CD28 on the T cell).
Initiation of the adaptive immune response
• The first step is the draining of antigen into the lymph node(s).
• In the lymph node(s) (or spleen), antigens are trapped by
professional APCs which display them to T cells.
The professional Antigen Presenting Cells (APCs)
• Three types of APC are found in the lymph nodes:
– Dendritic cells -- constitutively express MHC I and MHC II (can stimulate
both CD4+ and CD8+ T cells) as well as B7 (the co-stimulatory signal).
Antigen presentation appears to be the sole purpose of dendritic cells,
and these cells can be infected by a wide variety of viruses. Dendritic
cells are not phagocytic. They can present some viral peptides on their
MHC II, and contribute to the induction of antibody against viruses. They
are very efficient at stimulation of cytotoxic responses.
– Macrophages -- Resting macrophages express little MHC II or B7, but have
receptors for bacterial cell wall components which, upon binding,
activate the macrophage to express high levels of B7 and MHC II. Once
activated, macrophages are efficient at stimulating CD4+ T cells, both for
inflammatory responses and helper (antibody) responses.
– B cells -- B cells express high levels of MHC II, but not B7. Microbial cell
wall components can induce B7 expression by B cells (like macrophages).
Once induced to express B7, B cells can activate helper T cells. B cells can
take up soluble antigen through their Ig receptors (unlike dendritic cells
or macrophages).
The antigen presenting cells, continued
Dendritic Macrophage
Cell
B cell
Note: this B cell is not a
plasma cell -- a plasma
cell is shown above.
Plasma cells do not
present antigen. They
simply pump out
antibody for a few days
then die.
Capture of circulating T cells in lymph nodes
T cells enter lymph node across the
walls of venules
T cells that do not encounter
specific antigen leave the lymph
node through lymphatic vessels
T cells monitor antigen presented
by macrophages and dendritic cells
T cells that encounter specific
antigen proliferate and begin to
differentiate into effector cells
T cells continuously circulate via the blood and
lymph through different lymph nodes until they
either find presented antigen or eventually die
• When a T cell encounters an APC displaying antigen to which
it can bind, it stops migrating and binds strongly to the APC.
• Within about 2 days (48 hours), most antigen-specific T cells
have been trapped by antigen and within about 4 to5 days
armed effector T cells are migrating
out of the lymph node.
Review -- Cytokines produced early in response to infection
influence the future functions of activated CD4+ cells
• Cytokines produced by TH1
cells inhibit TH2 cells
• Cytokines produced by TH2
cells inhibit TH1 cells
• An immune response is
often dominated by a cellmediated response or an
antibody response.
• Some pathogens have
evolved strategies to shift
the immune response
toward the less effective
type for that pathogen.
TH0
IL-2
IL-4
IFN-
TH1
TH2
IL-2
IFN-
F
IL-4
IL-6
IL-10
Functions of the different T cell types
• CD8+ cells: Kill virally
infected cells
• CD4+ cells:
– TH1: Activate macrophages to
aggressively ingest antigen
and to kill ingested microbes.
– TH2: Stimulate B cells to
differentiate into antibodyproducing plasma cells. B cells
will only undergo isotype
switching after receiving T cell
help. The Ig class that a B cell
switches to is specified by the
types and balance of cytokines
secreted by the helper T cell.
Most plasma cells migrate to
the bone marrow where they
live out the rest of their lives.
One cytotoxic T cell can kill multiple targets
Micrographs:
Left: healthy cell.
Middle: lower right
cell is in beginning
stage of apoptosis
Right: small cell in
middle is in
advanced apoptosis.
Its nucleus is highly
condensed and it
has shed much of its
cytoplasm.
• A cytotoxic T cell causes its target to undergo apoptosis (cell suicide)
by the focussed secretion of vesicles carrying cytotoxins.
• The T cell binds to its target, delivers its cytotoxins, and moves on
before it has a chance to be hurt itself (one T cell can kill another, so a
T cell is not immune to the cytotoxins).
Immunological memory
• When B cells are activated to reproduce, some
differentiate into plasma cells and some become longterm memory cells.
• An adaptive immune response also produces T cell
memory, but the nature of memory T cells is unknown.
Two possibilities exist. Memory T cells probably originate
from either:
– 1. A long-lived subset of effector T cells that differentiates into
memory T cells -- like memory B cells.
– 2. The continuous low-level activation of naïve T cells by specific
antigen that is retained in the lymph nodes after an infection.
This mechanism would suggest that APCs in the lymph node hold
on to antigen on a long-term basis after an infection and
continuously stimulate T cells at a low level so there is always a
small effector population ready to go.
MHC classes I and II
Functions:
• class I MHC:
– Displays peptides derived from antigen originating inside the cell
(endogenous antigen).
– Important in cytotoxic responses (eg, CD8+-killing of virus-infected cells).
• Class II MHC:
– Displays antigen derived from ingested antigens (exogenous antigen).
– Important in humoral (antibody) responses as well in fighting as some intracellular
parasites (eg. Mycobacterium tuberculosis and M. leprae)
• Locations:
– Class I MHC found on all nucleated cells (all cells need to be prepared to be killed in
case of a viral take-over or tumorigenic transformation).
– Class II MHC found only on antigen presenting cells (cells that present antigen to
CD4+ T cells --> Macrophages, activated B-cells, dendritic cells.
Antigen Presentation to T cells: MHC
• Antigens are presented to T cells as short peptide
fragments bound to Major Histocompatibility (MHC)
molecules.
• Two types of MHC in humans and mice:
– MHC I: presents an 8-10 amino acid peptide to CD8+ T
cells.
– MHC II: presents a longer peptide (13 aa or more) to CD4+
T cells.
MHC structure
Peptide binding cleft
2 1
3
Peptide binding cleft
1
2-microglobin
Class I MHC
1
2 2
Class II MHC
• MHC classes I and II have an almost identical 3-D structure.
• Both classes of MHC are polygenic (each cell has many MHC
genes) and polymorphic (there are many alleles for each locus),
but the MHC genes do not undergo recombination.
Note: Human MHC are called HLA (human leukocyte antigen).
MHC / T cell interactions
target cell
Class I MHC
CD8
CD8+ T cell
Class II MHC
Antigen presenting cell
CD4
TCR complex
TCR complex
CD4+ T cell
• The MCH/peptide-TCR interaction is facilitated by the CD4
or CD8 co-receptor.
Antigen processing: Endogenous pathway
All nucleated cells can process endogenous proteins and
present fragments on their class I MHC.
Display of MHC I + peptide
on cell surface
degradation
Vesicle carrying
MHC I-peptide
Cytoplasmic
proteins
Processing in E.R. and
complexing with MHC I
Endoplasmic reticulum
Nucleus
Antigen processing: Exogenous pathway
Professional antigen presenting cells ingest microbes and free particles, degrade
them in lysozomes, and present fragments to CD4+ T cells on MHC II.
Display of MHC II + peptide
on cell surface
Ingestion of microbe
Vesicle fusion,
assembly of
peptide/MHC II
Vesicle carrying
MHC II
Degradtion in
lysozome
MHC II is assembled in ER
Endoplasmic reticulum
Nucleus
CD4+ T cell activation
• T cells require co-stimulation for activation -- binding of
the TCR to MHC/peptide is not enough to activate a T cell
by itself.
• B7 on an APC binds to CD28 on the T cell to deliver a costimulatory signal. .
• Activation by peptide/MHC-TCR binding plus a costimulatory signal leads to Interleukin-2 (IL-2) release and
up-regulation of the IL-2 receptor on the T cell.
• IL-2 stimulates growth and proliferation of T cells.
CD8+ T cell activation
• A naïve circulating CD8+ T cell also requires costimulation to become an “armed” effector cell.
• A CD8+ T cell can be activated by an APC displaying MHC
I/peptide along with B7 (CD8+ cells also have CD28).
• Activation of the CD8+ cell causes upregulation of the IL2 receptor and production of IL-2, leading to growth
and proliferation.
• An activated CD8+ T cell can sustain itself on its own IL-2
production, once activated.
TCR genetics: Similar to Ig genetics
(numbers of segments in book is off, just like for Ig genes)
C region (1)
J regions (61)
V regions (70-80)
 chain
V regions (52)
D1 (1)
J1 (6)
C1 (1)
 chain
D2 (1)
J2 (7)
C2 (1)
Mechanism of TCR (or Ig) gene rearrangement.
This DNA is lost forever
Mechanism of TCR (or Ig) gene rearrangement.
Mechanism of TCR (or Ig) gene rearrangement.
Mechanism of TCR (or Ig) gene rearrangement.
This DNA is lost forever
Rearranged  chain
Mechanism of TCR (or Ig) gene rearrangement.
Mechanism of TCR (or Ig) gene rearrangement.
Mechanism of TCR (or Ig) gene rearrangement.
Mechanism of TCR (or Ig) gene rearrangement.
Mechanism of TCR (or Ig) gene rearrangement.
Mechanism of TCR (or Ig) gene rearrangement.
Mechanism of TCR (or Ig) gene rearrangement.
Mechanism of TCR (or Ig) gene rearrangement.
eg.,  chain rearrangement
V regions (52)
D1 (1)
J1 (6)
C1 (1)
D2 (1)
J2 (7)
C2 (1)
Mechanism of TCR (or Ig) gene rearrangement.
T cells develop in the thymus
and undergo positive and negative selection
• Positive selection: T cells which can react to self MHC (major
histocompatability complex) carrying peptides are allowed to live.
Those that cannot undergo apoptosis (suicide).
• Negative selection: T cells that react strongly to self-antigens on
MHC are eliminated.
• Only those T cells that can react to MHC, but do not bind strongly to
self-antigens emerge as mature T cells from the thymus.
• Only about 2% of immature T cells make it through positive and
negative selection.
–The T cell receptor (TCR):
Structure and function
–TCR expression
•Genetic organization
•Gene rearrangement
TCR gene rearrangement, continued
• The  chain rearrangement occurs before  chain
rearrangement.
• If a functional  chain is produced, the  chain gene is
rearranged.
• If a functional  chain is not produced, the pre-T cell dies.
• The mechanism of rearrangement is basically the same as for B
cells -- the same enzymes are even used.
• Note:  chain rearrangement can occur several times, so once a
functional  chain is produced, a functional TCR will most likely
be produced. (Both TCR  chain rearrangements and Ig heavy
and light chain rearrangements generally only happen once for
each chromosome in each cell).