T cells

Cell Mediated Immunity (CMI)

Dr. Thu Zar Han

Introduction
Body defense against microorganisms
First line intact skin and mucous
membrane
Second line Innate arm of immune

system
Third line Adaptive immune system

includes lymphocytes (T and B) and

cytokines & antibodies

T LYMPHOCYTES

T lymphocytes

Stem cells in BM

thymus where

they develop into T cells.

Thymic education : a process that

involves both positive & negative

selection ensures that desirable T cells
are those that can recognize self MHC
molecules but are not autoreactive
Positive selection : Cells are positively

selected if they express a TCR capable of

interacting with the MHC complexes on
the persons own epithelial cells in the
thymic cortex

T lymphocytes
Negative selection

death of lymphocyte that expresses a TCR

that recognize self antigens in the thymic
medulla (clonal deletion)
Thymus evolutes in adult, remants of
thymus remains functional throughout the
life- T cells continued to be made
Some T lymphocytes do not develop in
thymus but in GALT ; IELs intraepithelial
lymphocytes protection against
intestinal pathogens

Positi
ve
select
ion
&
Negat
ive
select

Lymphocytes and lymphoid

tissue
1012 / a trillion lymphocytes (normal adult)

T
B
Natural
(Thymus-derived)
(BM-derived)
75%
10%
15%
(% in peripheral blood)

killer cell

Different T cell phenotypes and

their functions
Surface
molecules
TCR
-TCRs
(95%)

Site

Circulatory T
cells

Functions
Helper,
cytotoxic,
suppressor

-TCR
Mucosal
Cytotoxic
(Intraepithelial surface (GALT) (intestinal
lymphocytes)
pathogens)
CD4+
CD8+

Helper T cell
Cytotoxic T cell

Surface molecules of T cells

All T cells have CD3 in association

with TCR
Mature T cells have either CD4 or
CD8
Helper T cells CD3+, CD4+
Cytotoxic T cells CD3+, CD8+

CD4+ T CELLS
recognize antigens presented by

MHC class II molecules

Helper functions by producing

cytokines
1. Help B cells develop into antibody
producing plasma cells (IL-4 and IL5)
2. Help CD8 cells to become activated
(IL-2)

CD4+ T CELL subsets

CD4+ T CELL subsets

Down Regulation of TH1 and TH2

cytokines
IFN produced by TH 1 cells help B cells

to class switch to produce IgG1, IgG3

effective opsonization
IL-12 increases number of TH-1 subsets
Myco.tuberculosis produce lipoprotein that
stimulates the specific TLR on the
macrophage - synthesize IL-12
IL-12 derives TH-0 to TH-1 secrete IFN
IFN inhibit production of TH-2 cells
IL-4 inhibit production of TH1 cells

Activation, Proliferation and

Differentiation of CD4+T cell

(1) Activation:

Two signals
First signal specific antigen signal
TCR +CD3 peptide-class MHC
complexes
IL1 need for efficient T cell activation
Second signal co-stimulatory signals
CD28 B7-1,7-2 CD80,CD86
CD2 LFA-2 CD58 LFA-3
LFA-1 ICAM-1
VLA-4 VCAM-1

These 2 signals induce activated TH cells to

secrete lymphokines such as IL-2, IL4,IL5,
ILs----, IFN-r

2. Proliferation and differentiation of T

cell

Activation of CD8+ T CELLS

Recognize peptide+ MHC I complex
First signal induces IL-2 receptors on Tc cell
Second signal provided by IL-2 secreted

from a activated TH cell

Activated Tc - cytotoxicity

Features of CTL-mediated Lysis

1. CTL killing is antigen-specific.
To be killed by a CTL, the target cell
must bear the class I MHC-associated
antigen
2. CTL killing requires cell contact.
3. CTLs are not injured when they lyse
target cells.
Each CTL is capable of killing

Killing mechanisms of Cytotoxic T cells

1. Perforin and Granzyme

Perforins form the channel through the
membrane, cell contents are lost,
cells dies
Granzymes proteases degrade
protein in the cell membrane
2. They activate caspases that initiate
the apoptosis
3. Fas-FasL pathway
Binding of FasL on Tc cell and Fas

Killing mechanisms of Cytotoxic T cells

Functions of T cells
Regulatory functions by TH cells central role

in both cellular and humoral immunity

By producing Cytokines
Cytokines affecting the T cells IL-2
Those cytokines affect on B cells- Il-4,IL5, IL-6
Those cytokines affect on macrophages IFN

Effector functions mainly by CD8 T cells

Cytotoxicity

Other T cells
Treg Cells
CD4+, CD25+,Foxp3+
Produce TGF- and IL-10 Suppress (suppressor cells) of effector functions of T

cells
CTLA-4 (Cytotoxic T cell molecule 4) that binds to B7
No more activation of TH cells
NKT cells (0.2% of all peripheral blood T cells)
T cells share properties of T and NK cells
Recognizes lipids and lipid antigens

MACROPHAGES

Activation of
Macrophages
IL-1 stimulates macrophages to express

surface receptors for IFN on T cells

Contact between APC & Ag-specific TH cellsecretion of IFN by activated T cell
resulting in macrophage activation
Activated macrophage releases monokines

eg. IL-1, IL-6 & TNF

Bi-directional signalling events that effects

immunologic function of both cells

Activated macrophages have increased

phagocytic activity and increased ability to

Activation of
Macrophages

Outcome of TH cell activation

NK CELLS

NK cells : Characteristics
1. Large granular lymphocytes
2. Do not undergo thymic maturation
3. Lack markers for T and B cells
4. Express CD56, a specific NK marker
5. Express a receptor for Fc portion of

IgG, called FcRIII (CD16) -ADCC

6. Have 2 receptors: activating receptor
(lectin like receptor) recognize CHO
ligands;
Inhibiting receptors
killer immunoglobulin like receptor-

NK cells : Effector mechanisms

1. Similar to CTL
But Not MHC-restricted
2. Kill a variety of virus-infected cells and tumor
cells, but not all.
3. Susceptibility to killing by NK cells is inversely
correlated to
expression of class I MHC. Killer inhibitory
receptors (KIRs) on
human NK cells that recognize class I MHC
prevent killing.
Some virally-infected cells and tumors downregulate the expression of class I MHC and they
can be killed by NK cells. Because such class I

Killing mechanism by NK cells

Cell mediated immunity

(CMI)
Mediated by T lymphocytes
Cell mediated immune response

against
1. intracellular pathogens (viruses, fungi,
intracellular bacteria)
2. Tumor cells
3. Foreign graft

Common defects in CMI and

their effects
CMI and DTH reactions mainly against

intracellular organisms
Deficiency in CMI marked susceptibility
to theses infections and tumors

Congenital T cells deficiencies

1. Thymic aplasia : failure in the
development of thymus
Profound deficit of T cells- severe
infections in infants
2. Hyper-IgM syndrome: Mutation of
gene encoding CD40L in CD4+ Th cells
- failure to properly interact with CD40
result in inability of B cell to switch
from IgM to other classes of antibodies
3. SCID : severe combined

Acquired T cells deficiencies

1. AIDS
HIV specifically bind and kill cells bearing
CD4 protein
Normal CD4 to CD8 ratio(1.5:1) is greatly
reduced
2. Measles
Altered T cell functions, delayed
suppression of delayed hypersensitivity

Objectives:
The student will
list the immune cells involved in cell
mediated immunity.
relate the structures and
characteristics of these cells to their
functions
describe the processes and outcomes
of cell mediated immunity
outline common defects in cell
mediated immunity and their effects

References:
Compulsory:
Brooks, G.F., Carroll, K.C., Butel, J.S. &
Morse, S.A. (2013). Jawetz, Melnick and
Adelberg's medical microbiology. (26th
ed.).Chapterv8: immunology, p137-138
Levinson, W. (2013). Review of medical
microbiology and immunology. (13th
ed.). The McGraw- Hill Companies.
Updated 1/2015