Structure of B cell receptor (BCR),

T cell receptor (TCR),

Antigen Processing and
Presentation,
Immunoglobulin superfamily

Dr.D.RATHNAMMA
Professor and Head
Dept. of Veterinary Microbiology, Veterinary
College, KVAFSU, Hebbal, Bengaluru-560 024
 B cell receptor (BCR)
• Mature B cells are distinguished by
their synthesis of immunoglobulins and
display of the membrane bound immunoglobulins
(mIg) that serve as antigen receptor.
• Each B cell expresses a surface antibody (mIg)
with a unique antigenic specificity, and each of
the approximately 1.5x105 molecules of Igs
having identical binding sites for antigen.
• Mature B cell express IgM and IgD as membrane
bound immunoglobulins (mIg) having unique
antigenic specificity.
Structure of B-cell Receptor(BCR)
• B cell receptor is a trans-
membrane protein complex
composed of membrane bound
immunoglobulin (mIg) and a
disulfide-linked heterodimers
called Ig-α/Ig-β present on the
surface of B cell.
• BCR is structurally and
functionally divided into two
components;
1) Antigen recognition component
– mIg
2) Signal transduction component
- Ig-α/Ig-β heterodimer
 Signal transducing component
Membrane bound Ig cannot
signal directly to the B cell
since their cytoplasmic tails
are very short containing only
three amino acids.
BCR associated with
glycoprotein heterodimers
formed by pairing Ig-α
(CD79a) with Ig-β (CD79b)
having long cytoplasmic tails,
Ig-α has 61 aa, Ig-β has 48 aa,
interact with intracellular
signalling molecules for
activation of B cell once it
encounters an antigen.
 B cell receptor and co-receptors
B cell receptor also requires receptor
associated molecules (co-
receptors) for signal
transduction.
CD19, CD21(CR2) and TAPA-1 (CD81).
CD 21 component is a receptor for
C3d, a breakdown product of
the complement system (C3b),
which binds to antigen that
bound to mIg. This interaction
keeps the ag in contact with BCR
even when the Ag-BCR binding
is relatively weak.
CD19, a member of the Ig
superfamily, has a long
cytoplasmic tail and 3
extracellular domains always
associated with CD21
TAPA-1 a trans membrane protein
functions as a receptor for a
membrane molecule CR2.
• Signal transducing molecules
(Ig-α & Ig-β, CD21,CD19)
have ITAMs
(Immunoreceptor tyrosine
activation motifs) in their
cytoplasmic regions.
• The phosphorylation of
tyrosine residues in ITAMs
allows binding of
downstream adopter
molecules facilitating signal
transduction from the
receptors that stimulate the
activation of B cell.
 T cell receptor (TCR)
• T cell receptor is also a membrane bound protein
molecule composed of two polypeptide chains
(heterodimer) α and β (α/β heterodimer) or γ
and δ (γ/δ heterodimer).
• αβ T cells and γδ T cells
• In humans, mice, and probably most non-ruminants,
90% of T cells are αβ T cells (5-15% γδ T cells)
• In calves, lambs, and piglets in contrast, up to 66%
of T cells are γδ T cells (5-30% α β T cells)
T cells can be divided into many different subpopulations based
on the antigen receptors they employ and functions
• αβ T cells : dominant participants in adaptive immune
responses (HI & CMI).
• γδ T cells : mainly found in epidermis, GIT, lung
epithelium, reproductive organs. They are found mostly
in the gut mucosa, within a population of lymphocytes
known as intraepithelial lymphocytes (IEL).
• γδ T cells are the first T cells generated in fetus.
• Both type of cells are generated in the thymus.
• The choice to become a αβ or γδ T cell is dictated by
when and how fast the genes that code for each of the
four receptor chains successfully rearrange.
Development of T lymphocytes in Thymus
Positive and Negative selection of T lymphocytes in Thymus
 γδ T cells
• First line of defense
• Regulatory cells
• Bridge between innate and adaptive responses
• They do not express CD4/CD8 on their surface
• They are not MHC restricted in Ag recognition
• Act as sentinel cells
• Act as antigen presenting cell
• Act as phagocytic cells
• Recognize and interacts with lipid antigen
• Differentiate into memory T cell
Differentiating features of α/β T cells and γ/δ T cells

Sl Characteristics α/β T cell γ/δ T cell

1 Antigen receptor α/β TCR + CD3 complex γ/δ TCR + CD3 complex
configuration
2 Receptor(TCR) 1015 1020
number
3 Antigen recognition Peptide + MHC Protein and non protein
without MHC
4 Co receptors CD4+ or CD8+ Rare, in gut CD8
5 Frequency in blood 65-75% 1-5% ( 25-65% in gut)

6 Distribution Blood and lymphoid tissues Blood, epithelial and

lymphoid tissues
7 Effector ability CTLs (CD8+) CTLs, Cytokine release
Cytokine release (Th1/Th2)
8 Function Immune protection and Immune protection and
pathogen destruction Immune surveillance

Nature reviews Immunology, 2002

 αβ T cells
• αβ T cells show MHC restriction in antigen
recognition.
• On antigenic stimulation, proliferates and differentiates
into Effector cells and Memory T cells.
• Based on the surface glycoproteins (CD4+ & CD8+)
classified into T helper cells (CD4+ T cells) and T
cytotoxic cells (CD8+ T cells).
• T helper cells recognize exogenous antigens processed
and presented along with Class II MHC molecule.
• T cytotoxic cells recognize endogenous antigens
processed and presented along with Class I MHC
molecule
Structure of T cell Receptor

• T cell receptor is a trans membrane protein complex

composed of two polypeptide chains either α and β in αβ T
cells or γ and δ in γδ T cells
•TCR is specific for antigen and self MHC molecule (Self MHC
restriction).
•TCR also require receptor associated molecules (co receptors )
for signal transduction
•TCR is associated with CD3 protein complex (TCR-CD3)
•TCR is antigen recognition component
•CD3 is signal transduction component
•CD3 is a protein complex composed of five polypeptide
chains , heterodimer of γ ε chains, heterodimer of δ ε chains
and a homodimer of two zeta (ζζ) chains or heterodimer of
zeta (ζ) and eta (η) chains.
 Structure of T- Cell Receptor
Antigen binding groove
α chain -43 to 49kDa
Recognition β chain -38 to 44 kDa
Variable domain
α/γ β/δ  γ chain -36-46kDa
δ chain -44kDa

CD3 CD3
Constant domain

εδ γε
Transmembrane
domain

--
Cytoplasmic domain

ζζ Signaling
Structure of TCR-CD3 complex
• Signal transduction component
• CD3 complex
– Two chains of TCR is associated with a cluster of signal
transducing proteins
– Consists of five chains – γ, δ, ε, ζ and η arranged as 3
dimers γ-ε, δ-ε and either ζ-ζ or ζ-η.
• CD4 & CD8
– CD4 is a single-chain glycoprotein of 55 kDa
– CD8 is a dimer of 68 kDa – α-β heterodimer
- α-α homodimer
- Determines the class of MHC molecule that is
recognized by the T cell
- Enhances TCR signal transduction 100-fold
Interaction of T lymphocytes with MHC bound Ags
 Interaction of APCs with T lymphocytes.
Antigen is presented as peptide+ MHC class-I/II complexes (signal 1).
T lymphocytes are activated by interacting with co stimulatory molecules (signal 2).
ANTIGEN PROCESSING AND
PRESENTATION
Antigen presenting cells (APCs)
• Dendritic cells (DC) are the specialized cells of
the immune system, involved in antigen
processing and presentation to T lymphocytes,
thus functioning as Antigen presenting cells
(APCs) - potent APCs that can prime T
lymphocytes.
• first discovered by Ralph Steinman in the mid
1970s – awarded Nobel Prize in 2011.
Antigen Processing
and Presentation:

• Dendritic cells have distinct functions of antigen

capture in one location and antigen presentation
in another.
• Outside lymph nodes, immature DCs monitor
invasion by pathogens and capture intruding or
foreign antigens.
• They process these antigens, then migrate to
lymph nodes, where they present the antigen
to naïve T cells ( mature unprimed T cells)
initiating the adaptive immune response.
Development of subpopulation of T helper cells (TH )
 Two pathways of antigen processing:
Endocytic pathway and Cytosolic pathway
• Exogenous antigens- extracellular antigens are
processed by APCs in Endocytic pathway,
mediated by MHC II molecules, present to T
helper (CD4+) cells.
• Professional APCs - DC, Macrophages and B
lymphocytes.
• Endogenous antigens – intracellular antigens
viral infected cells, intracellular bacterial, tumour
cells - processed in Cytosolic pathway, mediated
by MHC I molecules, present to Tc (CD8+) cells.
Endocytic pathway of antigen processing
MHC class II mediated pathway for Exogenous Ag
Exogenous/extracellular antigens taken up by APCs
in three ways:
• By phagocytosis,
• By receptor-mediated endocytosis : Fc receptors
(FcγRII/CD32, FcγRI/CD64),complement receptors
(CR1) and C-type lectin receptors
• By pinocytosis.
– Foreign Ag is degraded in the endocytic compartments.
– The pathway includes:
– Early endosomes (pH 6-6.5)
– Late endosomes (pH 5-6)
– Lysomes (pH 4.5 – 5)
Ag is degraded into peptides of 13-18 amino acids that bind to MHC II
Endocytic pathway of Ag processing:
exogenous antigens by APCs

Kuby Immunology
 Peptide(Ag) binding to MHC class II molecule

• In RER, α and β chains of MHC II associated with a protein called “ invariant chain” (Ii,
CD74)
• invariant chain binds to MHC at peptide binding cleft + then exits the ER to Golgi
apparatus
• As proteolytic activity continues, the invariant chain is degraded to a small fragment, CLIP
(Class II associated Invariant chain Peptide)
• Another MHC II (HLA-DM , a non classical class II found in endosomes) substitutes Ag for
CLIP within lysosome
• MHC II + Ag complex is transported to the plasma membrane
Cytosolic pathway of Antigen Processing :
MHC class I mediated pathway for Endogenous Ag

• Endogenous Antigens:
Viral ags, I/c bacterial ags, tumour ags
• Processing of endogenous Antigens
involves 3 activities:
1. Peptide generation from proteolysis
2. Peptide transport to rough
endoplasmic reticulum (RER)
3. Peptide binding to MHC class I
molecule
Endogenous Ag processing…
Peptide generation

• Proteins targeted for

lysis combine with a
small protein 
ubiquitin
• Ubiquitin-protein
complex is degraded by
a proteasome complex
• Proteosome generate
peptides of 8-10 amino
acids which can bind to
MHC class I
Endogenous Ag processing…
Peptide Transport to RER
• Peptides from
proteolysis bind to a
transporter protein
associated with Ag
processing (TAP).
•TAP is a heterodimer
which uses ATP to
transport peptides of 8-10
amino acids to lumen of
RER.
Endogenous Ag processing…
Peptide binding (Ag) to MHC class I

• MHC I assembly occurs with the

aid of chaperone proteins to
promote folding (calnexin +
MHC I α chain)
• Tapasin + calreticulin brings
TAP/ peptide close to MHC
assembly
• Allows MHC I to bind to
peptides
• MHC I-Ag exits RER to Golgi to
plasma membrane
Assembly and stabilization of MHC I –
Ag complex
Comparison of Ag-processing pathways

Kuby Immunology
Cross presentation or Cross priming by
Dendritic cells
• DCs can also ingest viral infected cells, present
antigens to CD 8+ T cells .
• Viral proteins are released into the cytosol
• Processed and presented along with MHC I to
the surface inducing CMI response
• ‘Cross priming’ is therefore of prime
importance in the generation of CTL responses
against pathogens that infect non-
haemopoietic cells.
The Immunoglobulin superfamily

• Large number of membrane bound proteins have

been shown to possess one or more regions
homologous to an immunoglobulin domain.

• Each of these membrane proteins is classified as a

member of the immunoglobulin superfamily.

• The term Immunoglobulin superfamily is used to

denote proteins whose corresponding genes derived
from a common primordial gene encoding the basic
Immunoglobulin domain structure.
Members of the immunoglobulin superfamily
 B cell receptor (BCR)
 Ig-α/Ig-β heterodimer,
 Poly-Ig receptor, which contributes the secretory
component to secretory IgA
 T-cell receptor
 T-cell accessory proteins, including CD2, CD4, CD8,
CD28, and the γ, δ, and ε chains of CD3
 Class I and class II MHC molecules
 β2-microglobulin, an invariant protein associated
with class I MHC molecules
 Various cell-adhesion molecules, including VCAM-
1, ICAM-1, ICAM-2, and LFA-3
 Platelet-derived growth factor
The Ig superfamily -1
The Ig superfamily -2
 Fc Receptors
• Many cells express membrane proteins called Fc receptors
(FcR) that have an affinity for the Fc portion of the antibody
molecule.

• Fc receptors are responsible for the movement of antibodies

across cell membranes and the transfer of IgG from mother
to fetus across the placenta.

• Engagement of antibody-bound antigens by the Fc receptors

of immune cells provides an effective signal for the efficient
phagocytosis (opsonization) of antigen-antibody complexes,
ADCC, cross linking of Fc receptors by antigen-bound
antibodies can generate immunoregulatory signals that
stimulate cell activation, inducing proliferation and
differentiation and, in some cases, down regulate cellular
responses.
Fc receptors bound to Fc regions of Abs

neonatal Fc
receptor
• Poly Ig receptor is essential for the transport of
polymeric immunoglobulins (dimeric IgA and
to some extent, pentameric IgM) across
epithelial surfaces.

• FcRN (Neonatal Fc receptor) is MHC class

Id molecule transfers IgGs from mother to
fetus during gestation and also plays a role in
the regulation of IgG serum levels.
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