Effector and memory T cells

Assoc. Prof Mark Wright

Dept. of Immunology, Monash University
Mark.Wright@monash.edu

Reading for this lecture

Janeway, relevant sections of Chapters 9,
11 and 14
Abbas, chapter 13
For a simple review on the Th1/Th2
paradigm: Romagnani. Immunology Today.
1997. 18: 263

Learning objectives.. the

next 2 lectures.

Understand the role that effector T cells play in

the context of the adaptive immune response
Describe the specialised functions of 3 of the
major types of effector T cells:
Th1 cells
Th2 cells
Th17 cells

Treg cells (youll get most of this in a later lecture from Magda Plebanski)
Tfh cells (youll hear more from Fabienne Mackay)

Understand the concepts involved in

immunoregulation and Th1/Th2 balance
Understand the unique properties of memory T
cells
Homing
Lower threshold for activation
heterogeneity

 Lecture 1
Focus on Th1 vs Th2 cells

Lecture 2
Th17 cells how does this effect the
Th1/Th2 paradigm?
Memory T cells

Proliferating T cells differentiate into

effector T cells that drive the adaptive
immune response

The anatomy of adaptive cellular

immunity
T cell expansion and
differentiation occurs
within lymphoid organs
Differentiated
Effector T cells will
then migrate to the
periphery to the site
of inflammation

The function of effector

cells is determined by the
array of effector molecules
they produce
Effector CD8 T cells produce cytotoxins
Perforin and granzymes

Effector CD4 T cells produce cytokines

IL-4, IL-5, IL-13, IFN-, IL-17

CD4 T cells

Orchestrate the functional activity of

innate and adaptive immune systems
They do this via the differential secretion
of cytokines which help other arms of
the immune response
CD4 effector cells are heterogeneous CD4 T cells can differentiate into at least
5 different types of effector cells
Th1, Th2, Th17, Tfh
Treg

Their differentiation is also directed by

cytokines

Effector T cells

Lets take a short trip back in time to

2004, when Th cells were simpler.
Th1 and Th2 cells were
first identified in the
late 80s
Treg cells were rediscovered in the 90s
Th17 cells were
discovered in 2005
Tfh.2008/9

Thelper 1 cells promote cell

mediated immunity
The major role of
Th1 cells is to
secrete IFN-
A major activity of
IFN- is to activate
macrophages (M1
macrophages) and
make them efficient
killers of
intracellular
pathogens

Changes induced in activated

macrophages
Increase production of
cytokines:
TNF-, IL-1 (proinflammatory)
IL-12, IFN-

This induces
production of
antimicrobial agents
such as NO and O2 Increased expression
of MHC and
costimulatory
molecules

Th1 biology a more complex

version!!

IFN- also induces isotype switching to

IgG2a and 2c (mouse)

Th1 Differentiation
Which effector cell
developmental pathway an
uncommitted CD4 T cell (Th0
cell) chooses is determined
by the cytokine milieu during
T cell activation
IFN- can self-amplify the
differentiation of CD4 T cells
into Th1 cells
IL-12 is secreted by APC and
drives the switch from an
undifferentiated Th cell
(Th0) to a Th1 cell
IFN- is made by NK cells and
Th1 cells; IL-12 by APC

The inflammation induced by

Th1 cells can cause pathology
Th1 cells can induce
Type IV sensitivity
reactions (Delayed
type hypersensitivity)

Th1 cells can cause

pathology in
infection

Levels of insulitis
0!

1!

2!

3!

4!

Th1 cells can drive inflammation in autoimmune diseases

Th2 cells promote humoral

immunity
Th2 cells secrete IL-4, a
cytokine critically
important in promoting B
cell activation
IL-4 will drive isotype
switching towards human
IgG4 (mouse IgG1) and
IgE
IL-4 also is selfamplifying and promotes
differentiation of Th0
cells into Th2

A more complex version of

Th2 biology
Th2 cells also secrete IL-5,
and IL-13.
IL-5 mobilises and activates
Eosinophils.
IL-13 can modify macrophage
activation, promote epithelial
cell repair, smooth muscle
contraction and mucus
production
IgE, mast cells and eosinophils
are all critically important
components of the immune
defence against helminths.

Th2 cells protect us from helminths

Helminths are
Too big for
phagocytosis

Antibody Dependent
Cytotoxicity
Fc receptor for IgE

Worm displaying antigens

Upon crosslinking their
Fc receptor, Mast cells
and Eosinophils degranulate and
kill helminths
IgE and eosinophil responses
Are controlled by Th2 cells

IgE
Mast cell or Eosinophil

Eosinophils attacking
schistosome larvae

Weep and Sweep Response parasite expulsion

IL-4 and IL-13:

increase smooth muscle

contraction
Increase intestinal
permeability
Increase mucus
secretion by goblet
cells
Increase sensitivity of
these cells to mast cell
mediators

Th2 cells can also alternatively

activate macrophages, through
IL-4 and IL-13

M2 macrophages:
Produce arginase
rather then
inducible nitric
oxide sythetase
Produce
collagen..
Specialised in
tissue repair

Th2 cells can cause

pathology
Type 1 or immediate
hypersensitivity responses
occur minutes to hours after
re-exposure to antigen

Th2 cells
cause atopic
disease

Exposure to antigen
leads to the
induction of Th2
cells and the
production of IgE
Re-exposure to
antigen leads to mast
cell degranulation,
histamine release,
cytokine production

Th1 vs Th2 a summary

Th1 produce IFN and

promote cellular
immunity
Th2 produce IL-4 and
promote humoral
immunity
Th1 and Th2 are
preceded by
undifferentiated Th0
cells.

Cytokines determine Th
differentiation

Development of Th1 and Th2 subsets

IL-12 and IFN- drives
Th1 differentiation;
major source early are
NK cells
Tbet is a transcription
factor that is a
master regulator for
Th1 production
IL-4 drives Th2
production; major
source early are NKT
cells
GATA-3 is the
transcription factor
master regulator for
Th2 production

Th1 and Th2 cells negatively regulate one

another

Ie IFN- is produced by and promotes Th1.

It also inhibits Th2
IL-4 is produced by and promotes Th2
cells. It also inhibits Th1 responses

The Th1/Th2 paradigm

There is a balance
between Th1 and
Th2 immune
responses
The stronger the
Th1 response the
weaker the Th2
response, and vice
versa

Th1/Th2 balance affects

responses to infection
Genetically, Balb/c mice
make Th2 responses,
and so have poor cell
mediated immunity
mAb against IL-4
blocks Th2 and
promotes Th1.

Leishmania is an obligate intracellular parasire

Disease outcome in leprosy is a classical

example of Th1/Th2 balance
Tuberculoid leprosy.
Strong Th1 responses.
Granulomas, skin
lesions but low
bacterial counts
Lepromatous leprosy.
Weak Th1 responses,
high Th2 responses
and ab responses. High
bacterial levels.

Th1/Th2 balance affects

inflammatory diseases
T-bet is the master
transcription factor
that promotes Th1
cells
T-bet-/- mice have a
dysregulated Th1/
Th2 balance and
spontaneously
develop an asthma
like disease

Immunological diseases were largely

explained by Th1/Th2 dysregulation
Th1

Th2

Th2

Auto-immunity

Th1

excess Th1 responses are implicated in causing autoimmune

disease

Many immunological diseases are

explained by Th1/Th2 dysregulation
Th1

Th2

Th1

Th2

Th2 cells cause allergy

Hygiene hypothesis

Allergy

there is an epidemic of allergic disease in developed countries

The hypothesis argues that this is because children are brought
up in too clean an environment. Thus developing immune systems
dont encounter infections that drive the immune system down
a Th1 pathway, and so are prone to excess Th2 responses
The incidence of allergic disease in pre and post-unification
East Germany is compelling evidence for the Hygiene hypothesis

The incidence of East

German atopic disease

From Heinrick et al. European J. Epidemiology 14:241 1998

Hygiene
hypothesis

Genetics plus
environment cause
atopic disease
The original theory
stated un-hygienic
exposure to pathogens
drives Th1 responses
and suppresses Th2
responses
Almost certainly too
simplistic.
Cannot explain the rise
of Autoimmune diseases

So what do Tregs do?

Th2

Th1

Tregs inhibit BOTH Th1 and Th2 responses

Tregs

Th1

Th2

More details from Magda Plebanski.

Counter-regulation
hypothesis
Genetics plus environment
cause atopic disease
un-hygienic exposure to
all types of pathogens
drives regulatory responses
(Tregs: IL-10 and TGF-b)
which suppresses BOTH
Th2-driven atopic disease
and Th1 driven
autoimmunity