W12 The adaptive immune response - focus on T cells Flashcards
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 of lymphoid progenitor cell: 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 bone marrow → migrate to 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
thymus enlarges during childhood and then atrophies at pubert
Helper T cells (express CD4 and CD3)
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)
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
Gamma/delta 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
alpha/beta
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 ~1017 possible ab TCRs
gamma/delta
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
gamma/delta can also recognise…
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
MHCII on APC
presents peptide to CD4+ T cells to qualify the immune response: cytotoxicity or humoral
MHCI on any nucleated cell
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
Uptake of extracellular proteins into vesicular compartments of APC
Processing of internalized proteins in endosomal/lysosomal vesicles
Biosynthesis + transport of class II MHC molecules to endosomes
Association of processed peptides w/class II MHC molecules in vesicles
Expression of peptide-MHC complexes on cell surface
Antigen processing and presentation to CD8 cells
Production of proteins in cytosol
Proteolytic degradation of proteins
Transport of peptides from cytosol to ER
Assembly of peptide-class I complexes in ER
Surface expression of peptide-class I complexes
CLIP
CLass 2 associated Invariant chain Peptide
Dendritic cells
Irregularly-shaped cells in most tissues
DC usually myeloid derived (can be myeloid/lymphoid)
Only APC that can present to naïve T cells
When dendritic cells 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)
Dendritic cells - subtypes
include, Langerhans cells (skin), Interdigitating, plasmacytoid and ‘follicular DCs’ (actually fibroblasts)
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
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
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’)
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 gamma-interferon
Activates Macrophages 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.
Leishmania major
Th1 and Th2 are mutually antagonistic
Respone in most mice = TH1
Respone in BALB/c mice = TH2
TH1 response = recovery
TH2 response = disseminated infection
Mycobacterium leprae
Th1 and Th2 are mutually antagonistic
Some patients = TH1
Some patients = defective TH1 or dominant TH2
TH1 response = tuberculoid leprosy
TH2 response = lepromatous leprosy (high bac count)
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
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
HLA class + viral peptide + TCR + CD8 = bound together
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
