Adaptive Immune System

Yoes Prijatna Dachlan

Faculty of Medicine
Universitas Airlangga

(MKDU PPDS Imunol Dasar Januari 2019)

 Two types:
►humoral immunity, mediated by Abs produced by B lymphocytes
►cell-mediated immunity, mediated by T lymphocytes

►when activated → these components “adapt” to the presence

of infectious agents
for neutralizing or
by -activating,
eliminating the microbes
-proliferating,
-creating potent mechanisms
The adaptive
Immune System
►The ability to recognize and remember specific pathogens
→ to generate immunity, and mount stronger attacks each
time the pathogen is encountered

►B and T cells can create memory cells to defend against

future attacks by the same pathogen by mounting a stronger
and faster response

(Yoes Prijatna Dachlan, 2019) Boundless Anatomy and Physiology Boundless, 24 Oct. 2016. Retrieved 14 Mar. 2017
Immunology module;Module created by Patrick Fisher MS2
 Specificity, memory and maintaining homeostasis

(Yoes Prijatna Dachlan, 2019) (Abbas, 2012)

 Adaptive Immune System
relies on fewer types of cells to carry out its tasks:

B cells
►Humoral immune responses is mediated
antibodies (Ab), which are produced by cells,
called B lymphocytes → elimination of
soluble antigens (Ag) and destruction of
T cells
►Cell-mediated immunityis mediated by T
lymphocytes → elimination of intracellular
organism
►T cells use antigen receptors (TCR;T cell

extracellular microorganisms receptor), which are also expressed at the

►Naive B cells express immunoglobulin on plasma membrane T cells can only
their cell surface, which can also be called recognize antigen when presented within the
membrane-bound immunoglobulin → and peptide - binding groove of an MHC
this structure be served as the B cell receptor molecule.
(BCR) for antigen
► The humoral response to protein depends on
“help“ provided by T lymphocytes in the
form of cytokines and ancillary signals

(Yoes Prijatna Dachlan,2019) Both, B and T lymphocytes, are coordinated by T lymphocytes

 Adaptive Immune System
B cells
►B cells are formed in the bone marrow
►B cells have particular sites (receptors) on their
surface where antigens can attach
B cells can learn to recognize an almost limitless
number of different antigens
Primary immune response:
When B cells first encounter an antigen, the antigen
attaches to a receptor → stimulating the B cells
Some B cells change into memory cells, which
remember that specific antigen, and others →change
into plasma cells
Secondary immune response:
Whenever B cells encounter the antigen again,
memory B cells very rapidly recognize the antigen,
multiply, change into plasma cells, and produce
antibodies. This response is quick and very effective
Although the main function of B cells is to produce
antibodies, they can also present antigen to T cells
(Yoes Prijatna Dachlan,2019)
T cells
►T cells are produced in the thymus
►They can potentially recognize an almost limitless
number of different antigens (Ags)
►To avoid attacking the body's own tissues, they need
to learn how to distinguish Self from Nonself Ags
►There are different types of T cells:
Killer (cytotoxic) T cells attach to antigens on
infected or abnormal (e.g., cancerous) cells
Helper T cells help other immune cells. Some
helper T cells help B cells produce antibodies
against foreign antigens
Others help activate killer T cells to kill infected
or abnormal cells or help activate MØ, enabling
them to ingest infected or abnormal cells more
efficiently
Regulatory T cells produce substances that help end
the immune response or sometimes prevent certain
harmful responses from occurring
Delves PJ, University College London, London, UK
2017 Merck Sharp & Dohme Corp
Intracellular signaling pathways
(BCR – Ag crosslinking)

(Yoes Prijatna Dachlan,2017)

 ANTIGEN :
Ag • Molecules that are
Receptor specifically recognized by
antigen receptors either B
cells or T cells

Ag B cell • Molecules that initiate

adaptive immune
responses

MHC TCR
molecule

APC T cell

Antigen
(Male, Brostoff, Roth, Roitt, 2006)
(Yoes Prijatna Dachlan, 2011)
Both, humoral – and cellular immune responses are coordinated by T
lymphocytes
(Yoes Prijatna Dachlan,2019))
 Adaptive Immunity Background
►Innate immunity has an important role as the first line of defense against pathogens as well as in development
of an adaptive immune response
►The polarization of immune response largely depends on the initial signals that are brought by innate immunity

►There are some essential signals, required to induce T- and B-cell responses, required to induce T- and B-cell
responses
►Innate immune signals modulate the quantity and the quality of adaptive immune response and are required to
initiate an effective immune response, that mainly depends on the nature of the pathogen
►There are two separated ways of antigen processing, which enable the immune system to appropriately respond
against extracellular and intracellular pathogens, respectively
►The result (polarization) of immune response depends on which player of innate branch of immune response
(e.g., dendritic cell) recognized invading pathogen, how the peptides derived from antigenic components were
presented (MHC I or MHC II molecules) and which immunomodulatory molecules were produced (e.g. IL-12)
►Cooperation between initial innate and subsequent adaptive response is needed for effective functioning of the
immune system and immune response
►Now it became clear that innate immunity has an important role as the first line of defense against pathogens as
well as in development of an adaptive immune response

Delves PJ, University College London, London, UK

(Yoes Prijatna Dachlan, 2019) (2007-2016 Sino Biological Inc.)
2017 Merck Sharp & Dohme Corp
 Antigen processing
• Ags are processed before they are presented
to T cells.
• The processing the Ags to generate peptides
that can bind to MHC molecules
• MHC Class II molecules are loaded with
exogenous peptides
• MHC Class I molecules associate with
endogenous peptides

(Yoes Prijatna Dachlan,2019)

 Antigen processing
is an immunological process that prepares antigen for presentation to special cells of the immune
system called T lymphocytes It is considered to be a stage of antigen presentation pathways
Endogenous pathway
• A virus had infected the cell → viral peptides would also be
presented → allowing the immune system to recognize and kill
the infected cell
• Endogenous protein become ubiquitinated, marking them for
proteasome degradation
• Proteasomes break the protein up into peptides that include some
around nine amino acids long
• Transporter associated with antigen processing (TAP), a protein
that spans the membrane of the rough ER → transports the
peptides into the lumen of the rough endoplasmic reticulum (ER)
• Within the rough ER, a series of chaperon proteins, incl.
calnexin, calreticulin, ERp57, and Binding
immunoglobulin protein (BiP) facilitates the proper
folding of class I MHC and its association with β2m (β2
macroglobulin)
● The partially folded MHC class I molecule then interacts
with TAP via tapasin (the complete complex also
contains calcireticulin and Erp57 and, in mice, calnexin )
● Once the peptide is transported into the ER lumen it binds
to the cleft of the awaiting MHC class I molecule,
stabilizing the MHC and allowing it to be transported to
the cell surface by the golgi apparatus
● To present cellular peptide fragments on the cell surface on MHC
class I molecules
Exogenous pathway
• specialized APC to present peptides derived from proteins that the
cell has endocytosed
• The peptides are presented on MHC class II molecules
• Proteins are endocytosed and degraded by acid-dependent
proteases in endosomes; this process takes about an hour
• The nascent MHC class II protein in the rough ER has its peptide-
binding cleft blocked by Ii (the invariant chain; a trimer) to
prevent it from binding cellular peptides or peptides from the
endogenous pathway.
• The invariant chain also facilitates MHC class II's export from the
ER in a vesicle. This fuses with a late endosome containing the
endocytosed, degraded proteins.
• The invariant chain is then broken down in stages, leaving only a
small fragment called "Class II-associated invariant chain peptide"
(CLIP) which still blocks the peptide binding cleft
• An MHC class II-like structure, HLA-DM, removes CLIP and
replaces it with a peptide from the endosome. The stable MHC
class-II is then presented on the cell surface.
 Endogenous antigens & MHC Class I

(Yoes Prijatna Dachlan, 2012) (Abbas et al., 2012)

(Yoes Prijatna Dachlan,2013) Cellular and Molecular Immunology
 Exogenous Antigens & MHC Class II

(Yoes
(Yoes
Prijatna
Prijatna
Dachlan,2013)
Dachlan, 2012) (Abbas et al., 2012)
Cellular and Molecular Immunology
 CARDINAL FEATURES OF ADAPTIVE IMMUNE RESPONSES

Immune responses are specific for distinct antigens

Specificity
Diversity to respond to a large variety of antigens

Increases the ability to combat repeat infections by

Memory the same microbe

↑↑ the number of antigen-specific lymphocytes to

Clonal expansion keep pace with microbes

Humoral immunity and cell-mediated immunity are

elicited by different classes of microbes or by the
Specialization same microbe at different stages of infection
(extracellular and intracellular)

Homeostasis returning the immune system to its resting basal state

Nonreactivity to self

(Abbas, 2015)
(Yoes Prijatna Dachlan,2019)
 Lymphocyte clones matures In generative
in the absence of Ags lymphoid organs

Clones of mature lymphocytes Ags enter lymphoid

specific for diverse Ags tissues

Ag-specific clones are

activated (selected)
by Ags

Ag-specific immune
responses occur

The Clonal Selection Theory

(Abbas, 2015)
(Yoes Prijatna Dachlan,2019)
Adaptive immune system is highly dependent on
cells of the innate immune system for the purposes
of knowing when to respond, how to respond and
for how long (Roitt, 2011)

The actions of T - and B - lymphocytes are heavily

influenced by the cytokine environment
accompanying their initial exposure to specific
antigen

Cells of the innate immune system

shape the T h 1/ T h 2/ T h 17
response (Roitt, 2011)

Th1 cells coordinate responses to

T - helper cells can be further subdivided into Th 1,
intracellular pathogens
Th 2 and Th 17 cells on the basis of the cytokine
profiles that these cells secrete
Th2 cells coordinate responses to
extracellular pathogens

Th17 cells promote acute inflammatory

(Yoes Prijatna Dachlan,2015)
responses and recruit neutrophils
(Yoes Prijatna Dachlan,2015)

MHC – peptide recognition by the TCR represents signal 1, co - stimulation of CD28 by B7 ligands
represents signal 2, and cytokines produced by the DC represents signal 3. Note that the cytokine
environment upon restimulation of a T - cell within an infected tissue will also influence the nature
of the effector response made by the T - cell
Kimball’s biology pages
Naive T - cells can undergo activation and polarization to distinct Th subsets.
Cytokines produced by dendritic cells (DCs) or other innate immune cells, representing
signal 3, dictate the differentiation fate of the T - cell

(Yoes Prijatna Dachlan,2015)

 BCR and TCR are among the most
sophisticated signaling machines known

the intracellular biochemical responses

SIGNAL of cells after the binding of ligands to
TRANSDUCTION specific receptors

can result in induction of

differentiation, initiation of
proliferative and growth response

(Yoes Prijatna Dachlan,2013) (Abbas, et al., 2012)


Signals reaching the
nucleus alter gene expression
↓
leading to the synthesis of
new proteins
( cytokines, chemokines, and
cell-adhesion molecules)
(Yoes Prijatna Dachlan,2015)
The final destinations of
most of the signaling
pathways
are the nucleus and
the cytoskeleton
Signals reaching the
nucleus induce cell division
Signals reaching the
and differentiation
nucleus induce cell
↓ death after the immune
Expanding lymphocyte
response has occured
population
Signals reaching the
nucleus can affect the
cytoskeleton to alter the
cell, shape, size, and
motility
(Janeway’s, 2012)
 TCR
Signaling
phosphatidylinositol biphosphate Diacylglycerol

phosphatidylinositol trisphosphate

(Gorentla BK, Xiao-Ping Zhong, 2012)

(Yoes Prijatna Dachlan,
2016)
Events in T cell activation
 CD3 ζ chain

ZAP-70

2
Formation of
signalosomes nucleated
by adaptor molecules
and activation of PLCγ

ABBAS,
2015
(Yoes Prijatna Dachlan,
2016)
 3 Distal Signaling Pathway
The Ras-Erk1/2-AP1 pathway
extracellular signal-regulated kinase 1/2
AP1=activator protein 1
Phosphorylation of extracellular
signal-regulated kinase 1/2
(Erk1/2) has been a designated
biochemical marker to assess the
quality of TCR signaling for
decades
(Gorentla BK, Xiao-Ping Zhong, 2012)
(Yoes Prijatna Dachlan,
2016)
IP3-Ca+2-NFAT pathway
NFAT proteins have crucial
roles in the development and
function of the immune
system
NFAT proteins in T cells
►regulate activation
►are involved in the control
of thymocyte development,
T-cell differentiation and
self-tolerance.
►to integrate calcium
signaling with other
signalling pathways
(Masuda ES, 1998)
The PKCθ-IKK-NFκB pathway
NF-kappaB family members
►control the transcription of
cytokines
and antimicrobial effectors
►genes that regulate cellular
differentiation, survival and
proliferation → regulating various
aspects of innate and adaptive
immune responses
►contributes to the development and
survival of the cells and tissues that
carry out immune responses in
mammals
(Hayden MS, 2006)
oncogene
3
Distal Signaling Pathway

ABBAS,
2015
(Yoes Prijatna Dachlan,
2016)
(Yoes Prijatna Dachlan,
2016) ( Janeway’s Kenneth Murphy, 2012)
 Intracellular events associated with CD-4 T cell
activation

• Proximal phase : the activation and mobilization

of src familykinase; phosphorylation of CD3
subunit; recruitment and activation of ZAP-70
• Second phase : phosphorylation of LAT (linker of
activator) and SLP-76 (SH2-containing leucocyte
of 76 kDa → activate PLCγ
• Distal : directly coupled to transcription factor
mobilization in the nucleus

(Yoes Prijatna Dachlan,2013)

 T lymphocyte activation
• Two enzymes are activated : Calcineurin, a
serine/ threonine phosphatase → NFAT →
expression of the IL-2 gene; Protein Kinase C →
↑↑ the expression of the IL-2 gene
• The activated NFκB translocates to the nucleus →
↑↑ the expression of several genes
• LAT leading to progression from Go to G1
• IL-2R → activation of several transcription
factors of the JAK-STAT → T cell proliferation
and controls cell proliferation

(Yoes Prijatna Dachlan,2010)

(Yoes Prijatna Dachlan,2013)
 Signal transduction by the BCR complex
(Yoes Prijatna Dachlan,2013) (Abbas,2012)
 Membrane Ig + multivalent Ags

activates

Src family kinase

To phosphorylate

Tyrosine residues on the ITAMs of Igα and Igβ

The phosphorylation of ITAM tyrosine residues triggers

all subsequent signaling events downstream of the BCR

(Yoes Prijatna Dachlan,2013)

(Yoes Prijatna Dachlan,2013) The immunological synapse (Abbas,2012)