Cell-Mediated Immunity(CMI)

Overview
Immune System

Natural (Innate) Acquired (Adaptive)

non-specific specific

Humoral Cell-Mediated
T Cells: Cell-Mediated Immunity
 Develop in Bone Marrow, but mature in
Thymus
 Recognizes Antigen-Antibody complexes,
attach to it, and kill the cell carrying it.
 Macrophages and Activated B Cells act as
Antigen-presenting Cells (APCs)
 Engulf pathogens, partially digest them,
then display fragments on cell surface
 Cell-Mediated Immunity (CMI)
Mediated by T cells or T lymphocytes
• Cytotoxic (Tc)
• Helper (Th)
• Suppressor (Ts)

• Particularly effective against tumour cells,

viral-infected cells & transplanted cells
• Tc cells are effectors of CMI- they cause
lysis of cells which they attack

• Th & Ts are regulators of CMI- they control

both humoral & CMI

• Generally, B cells must be stimulated by Th

cells to produce a strong Ab response to a
particular Ag
 T Cells
• Tc cells are CD8+, Th cells are CD4+

• CD = cluster of differentiation

• Expressed by various cells at particular

stages of differentiation
 T Cell Receptors
• Similar to Abs

• Contain constant & variable regions

• Mediate Ag recognition

• Found on cell surface of T cell, but is not

secreted
 ADAPTIVE IMMUNITY AG
RECOGNITION
•Ag recognition by the adaptive immune system
involves recognition by
1. T cells
2. B cells
•T cell Ag recognition
• Solely membrane bound proteins called T cell
receptors
(TCRs)
• Related to Ig both in protein structure and
genetic variability
• However TCR does not recognise/ bind to Ag
directly
• Instead it recognises Ag bound to MHC
•B cell Ag recognition
• Molecule for Ag recognition is the antibody (Ig)
• Membrane bound Ig on the B cell surface serves
as the cell’s Ag receptor
AG RECOGNITION BY T
LYMPHOCYTES
•Infectious agents replicate in either of 2 distinct
cellular compartments:
1.The cytosol: viruses and bacteria
2.Endosomes and lysosomes: eg. Mycobacterium
tuberculosis
and M leprae
•Cells infected with cytosolic pathogens are eliminated
by cytotoxic T cells (CD8+)
•Pathogens in vesicular compartments are detected by
CD4+ cells
•CD4+ T cells fall into two classes:
1.Inflammatory T cells – activate macrophages
2.T helper cells – activate B cells
 T cell receptor (TCR)
•A T cell has about 30,000 TCR
molecules
•Each receptor consisting of 2
distinct polypeptide chains:
i. T cell receptor α chain
ii. T cell receptor β chain
•Human T cells therefore consist
of:
 α chain
 β chain
 γ chain
 δ chain
 ε chain
 T cell receptor (TCR)
•Consists of highly variable α and β chains
•α and β chains are glycoproteins
•a disulphide linked membrane bound
heterodimeric protein
•External portion consists of 2 domains with a
variable and constant domain each
•A short disulphide bond connects the 2
domains
•The TMD for each protein is hydrophobic and has
positively charged amino acids
•Positively charged TMDs destabilise the protein
•However these TMDs interact with the CD3
polypeptides γ, δ and ε
TCR AND CD3 COMPLEX
• α and β have no large cytoplasmic domain that serve to signal AG binding by TCR
• Function is achieved by proteins of the CD3 complex (CD3α, CD3β and CD3γ)
• CD3 proteins are homologous to Igβ and Igα
• Each CD3 protein consists of:
i. Extracellular domain
ii. Transmembrane region/domain (TMD)
iii. Modest cytoplasmic domain

•TMD of CD3 proteins have negatively charged aa that form salt bridges with
positively charged aa in the TMD of TCR
• Cytosolic domains contain sequences that allow them to associate with cytosolic
tyrosine kinase
CD3 COMPLEX PROTEINS
•CD3 complex is also involved in cell surface expression
of TCR:
1. TCR is associated with protein ώ in the ER
2. Nascent γ and ε chains are associated with the
δ and ε chains of CD3
3. The 3 complexes αβ, δε and γε are transported
to the Golgi
4. CD3:γε heterodimers displace the ώ chain
from the TCR αβ heterodimer
5. The resulting αβγ δε2 complex is only
transported efficiently to the cell surface when
it binds to the ξξ dimer
CO-RECEPTORS
CD4
•A single polynucleotide with 4 domains
•D1 and D2 are tightly joined and form a single 60A
rod
•Joined by a flexible hinge to a similar rod (D3 and D4)
•Cytoplasmic domain interacts strongly with
cytoplasmic tyrosine kinase
•Binding site for MHCII is on the lateral side
•CD4 binds on the β2 domain of MHCII
•CD8 consists of a disulphide-linked
heterodimer comprising α and β chains
 Major Histocompatability Complexes
(MHC)
•Glycoproteins
•Encoded by genes on chromosome 6 (6p21.31)
•In humans this region contains more than 200 genes
•Also called human leukocyte antigens (HLA)
•So called as they were discovered through antigenic
differences between white blood cells from different AGs
 Major Histocompatability
complex
• T cells cannot recognize Ag alone

• Ag must be presented in conjunction

with major histocompatability complex
(MHC) proteins

• In humans called human leucocyte

antigens
• MHC proteins are glycoproteins found
on cell surface

• Vary from 1 individual to another &

serve as a label

• 2 classes, MHC I & MHC II are involved

in Ag processing
• Differ in structure, location & function
 MHC 1 STRUCTURE
•Consists of 2 polypetide chains
1. A larger α chain encoded on chromosome 6
2. A smaller β2 microglobulin encoded on chromosome 15
•The α chain consists of a single polypeptide chain
composed of:
i. 3 extracellular domains (α1, α2 and α3)
ii. A transmembrane region
iii. A short intracytoplasmic tail
•β2 microglobulin consists of a single non-
polymorphic molecule noncovalently bound to the
chain
•α1 and α2 fold together into a single structure that consists
of 2 segmented α helices lying on a sheet of 8 a’parallel
β strands
•This folding creates the long Ag binding cleft
• MHC I – found on all nucleated cells

• Important in presenting endogenous Ag, eg

virus to Tc cells

• Endogenous Ags - produced within

cytosol, eg viral proteins in an infected
cell
 MHC II STRUCTURE

•Consists of 2 noncovalently linked polypeptide

chains a and b
•Both encoded by MHCII gene region on
chromosome 6
•A and B chains consist of 2 extracellular domains a1,
a2 and b1 b2
•Both chains have a transmembrane domain and a
cytoplasmic tail
•The extracellular membrane proximal a2 and b2
domains are homologous to immunoglobulin constant
domains
• MHC II – found only on immunocompetent
cells such as macrophages & B cells

• Present exogenous Ag to Th cells

• Exogenous Ag – taken up by endocytosis,

found in vesicles within cells

• Eg bacteria & their products taken up by

macrophages
EXPRESSION OF MHC

•MHC- I proteins are expressed on all nucleated cells, in contrast to MHC-II molecules, which
are restricted to antigen-presenting cells (APCs)
•Lymphocytes, macrophages, dendritic cells, Langherans cells, and some endothelial cells are
the predominant cells that express MHC-II.
•Nonnucleated cells such as mammalian red blood cells express little or no MHC-I and thus,
pathogens within red blood cells can go undetected by cytotoxic T cells, e.g., malaria.
•The expression of both MHC-I and MHC-II molecules is regulated by cytokines.
•Interferon-g (INF-y) increases the expression of MHC-I or MHC-II molecules and can induce the
expression of MHC-II molecules on certain cell types that do not normally express them. This may
be very important both in normal immunologic function and in autoimmunity.
•The level of MHC molecule expression plays an important role in T cell activation and
therefore differences in levels of expression are significant.
 Helper T
Cells
CD4 receptors
 Cloning stimulated by binding to APC
 Antigen-specific
Release cytokines (Interleukins) that stimulate
reactions in other cells
 Activate B-cells to make Antibodies
 Activate Killer T Cells to reproduce
 Target cell for HIV
 Cytotoxic (Killer) T
Cells
CD8 receptors
Cloning is stimulated by binding to APC
Attack and Kill other cells
 Perforin—create holes in target cell membrane