The adaptive immune response:

Focus on T cells

Dr Mark Bodman-Smith
Senior Lecturer in Immunology
mbodmans@sgul.ac.uk
Learning objectives
Review of immune cells
Lymphocytes
T cells
Role of thymus
Antigen presentation
T cell subsets
Players in Immunology

NKT cell

Dendritic cells

Granulocytes

Macrophages
Players in immunology 2
Lymphocytes
 Lymphoid progenitor cell
 Gives rise to Lymphocytes
 20-30% peripheral blood white cells
 6-10 microns in diameter with large nucleus,
small halo of cytoplasm

 Upon stimulation by Ag become EFFECTOR

CELLS or MEMORY CELLS

 2 main types: T cells and B cells

(T-lymphocytes and B-lymphocytes)
 Early developmental stage, cells pass to
Thymus – become T cells or stay in Bone
marrow – become B cells
 Role of the thymus in T cell development

T cells mature in the thymus.

Immature T cells develop in the bone marrow then

migrate to the thymus to encounter self-antigen.

During this process many T cells die by apoptosis

leaving just those that can generate a useful
response to infection.

The thymus enlarges during childhood and then

atrophies at puberty

To be continued…………………
 T cell subsets
ab T cells
Helper T cells (express CD4 and CD3)
• activated to secrete cytokines to help
immune responses or to become
memory cells
• 2 main sub-groups: TH1 & TH2 ( also Th17)

Cytotoxic T cells (express CD8 and CD3)

• activated to kill infected targets or to become memory cells
• usually cytotoxic in nature and kill via the release of the toxic
contents of granules or through induction of apoptosis

Regulatory T-cells
• mainly CD4+ (some CD8+) T cells able to affect immune responses by either suppressing
them or activating them through direct cell contact or by the secretion of soluble factors
(cytokines)
• 2 main types: natural or inducible

g/d T cells
• TCR formed of g/d chain recognise lipid antigens
 The T cell receptor

• Dimeric molecule; ab or gd chains covalently linked by S-S

• Each chain has a variable and constant Ig like domain
• The variable region has hypervariable regions which are the antigen
binding sites
• Associated with the signalling complex CD3
• CD3 is the identifier of the T cell
 ab v gd
ab
Makes up ~90% of peripheral blood MNC
Express CD4 or CD8
Restricted through MHC I or MHC II
a chain consists of germline Variable, Joining
and Constant regions
b chain consists of germline Variable, Diversity,
Joining and Constant regions
Total repertoire of ~1017 possible ab TCRs
gd
Makes up ~10% peripheral blood MNC but up
to 70% of mucosal T cells
Some express CD8 and few CD4, most double
negative
Some gd T cells are restricted through CD1c
Some use the NK receptor family
Some recognise cells stress indicators (HSP,
butyrophilin)
gd T cells can recognise a number of bacterial
antigens
Can also recognise small aliphatic molecules
(isoprenoid pyrophosphates and amines) which
may represent a pattern recognition system
Extensive junctional diversity increases the gd
TCR repertoire to ~1019 possible receptors
MHC: The Major Histocompatibility
Complex
• Surface expressed molecule which bind peptides derived from antigen
and present to T cells.
• MHC encodes for the human leukocyte antigens (HLA)
• Two types: MHC Class I (HLA-A, B and C): expressed on all nucleated
cells
• MHC Class II (HLA-D): expressed on ‘professional’ Antigen Presenting
cells
MHCI and II
Peptide binding groove
• MHCII on APC presents peptide to CD4+ T cells to qualify the immune
response: cytotoxicity or humoral

• MHCI on any nucleated cell presents peptide to CD8+ T cells and is a

signal for a cytotoxic response (except cross-presentation in APC).
Antigen processing and presentation to CD4 cells
Antigen processing and presentation to CD8
cells

Cross-presentation
Antigen Presenting Cells
 Dendritic cells
 Irregularly-shaped cells in most tissues
 DC usually myeloid derived (can be myeloid/lymphoid)

 When immature, DCs capture Ag (foreign material) and migrate to LYMPHOID

TISSUES where they mature and effectively ‘present’ or ‘show’ antigen to T cells
(T lymphocytes)
 Subtypes: include, Langerhans cells (skin), Interdigitating, plasmacytoid and

‘follicular DCs’ (actually fibroblasts)

Only APC that can present to naïve T cells
APCs & T cells
 Other APC
• Tissue specific DC:
• Langerhans cells in skin
• Interstitial DC in dermis
• Blood myeloid DC
• Plasmacytoid DC
• Blood monocyte derived DC
• Macrophages
• B-cells
• Endothelial cells under some conditions
APC:T cell interaction
APC

MHC TCR

T cell
APC:T cell interaction
APC

MHC TCR
Signal 1 T cell
APC:T cell interaction
APC

CD80/86 CD28 Signal 2

Signal 1 T cell
APC:T cell interaction
APC

CD80/86 CD28 Signal 2

Signal 1 T cell

CYTOKINES Signal 3
 3 signals to get correct T cell activation

1: Peptide bound in MHC (I or II) ligates cognate T cell receptor

 3 signals to get correct T cell activation

1: Peptide bound in MHC (I or II) ligates cognate T cell receptor

2: Costimulation by ligation of CD80/86 to CD28

 3 signals to get correct T cell activation

1: Peptide bound in MHC (I or II) ligates cognate T cell receptor

2: Costimulation by ligation of CD80/86 to CD28

3: Modulation of signal by cytokine production

Back to the thymus: +ve and –ve selection
• T-cells in the thymus enter as
thymocytes not expressing
either CD4 or CD8 (double
negative), go through a stage
of expressing both (double
positive) followed by a decision
be either CD4+ or CD8+
• Are positively selected to bind
to molecules called MHC and
negatively selected if bind self
peptides (‘education’)

So: productive rearrangement?

Recognise MHC
Don’t recognise self
CD4 T cells:
• Recognise a peptide in the binding groove of MHCII
• T-helper cells: produce a cytokine profile which directs the immune
response to a particular outcome.
• T-regulatory cells: responsible for ending an immune response.
CD4+ Th1 cells
• Express the co-receptor CD4
• Help to activate the cellular immune response
• Produce g-interferon
• Activates Mf and cytotoxic T cells

• Th1 response effective against intracellular infections, bacterial,

protozoal and viral.
CD4+ Th2 cells
• Express the co-receptor CD4
• Help to activate the humoural immune response
• Produce interleukin 4, 5 & 13
• Activates B cells to produce antibody

• Th2 response effective against extracellular cellular infections,

bacterial, protozoal and viral. Effective in production of IgE against
helminth infection.
Th1 and Th2 are mutually antagonistic
CD4+ Th17 cells
• Express the co-receptor CD4
• Help to protect the gut mucosa
• Produce interleukin 17, 22.
• Recruits neutrophils to sites of infection

• Th17 response effective against extracellular bacteria and fungi.

Effective in promoting neutrophil mediated inflammation and helping
Th1 cells to induce phagocytosis and subsequent killing of pathogens.
CD4+ Treg cells
• Express the co-receptor CD4, CD25 and FoxP3
• Maintain immune tolerance and suppress immune responses
• Produce anti-inflammatory cytokines IL10 and TGFb.
• Also has contact-dependent immunosuppressive effect

• Tregs inhibit the effector functions of CD4+ and CD8+ T cells. Also
inhibit antigen presentation function of B cells and other APC.
CD8+ cytotoxic T-cells (CTL)
• Express the co-receptor CD8.
• Eliminate intracellular infections
• Produce IL2, TNFa and gIFN.
• Also has role in anti-tumour immunity and rejection of transplants.

• Kill infected cells in an antigen-specific and cell-contact dependent

manner.
CD8+ cytotoxic T-cells killing mechanisms
• Contact delivers a lethal hit!
• CTL can then detach and target
another cell.
• Releases cytolytic molecules from
intracellular stores.
• Triggers apoptosis in target cell.
CTL cytolytic proteins
• Perforin: forms pores in target cell membrane allowing
the entry of….

• ….Granzymes (A,B & C), which are serine-esterase

proteases and induce apoptosis.

• This acts at a specific synapse between the CTL and

target thus limiting any ‘collateral’ damage.

• Involves cytoskeletal reorganization and granule

release.
CTL killing mechanisms 2
• Granzymes activate caspases => apoptosis
• Granzyme B: can trigger mitochondrial apoptotic
pathway

• FasL (on CTL) ligates Fas receptor (on target cells) =>
activation of caspases => apoptosis

• Killing of infected cells by CTL => eliminates reservoirs

of infection
NKT cells
• Express T cell markers and NK cell markers.
• Large cell population (20% mouse liver lymphocytes)
• Restricted TCR usage (Va14/Va24)
• Antigenic specificity?
• Respond to glycolipids such as a-galactosyl-ceramide
• Restricted through CD1d
Summary:
• T cells are lymphocytes which are part of the adaptive immune
response
• Go through a thymic education stage to remove self-reactive cells
• Recognise antigenic peptides in the groove of MHC molecules on APC
or target cells
• Need 3 signals to be activated properly
• Can express CD4 (Th cells) or CD8 (CTL)
• Produce many cytokines which orchestrate the immune response.
 Recommended reading:

Immunology: Male, Brostoff, Roth and Roitt.