T-Cell Activation and Generation of Effector T-Cells Flashcards
What are the 2 types of adaptive immune responses?
- Humoral immunity
- Cellular immunity
What is humoral immunity?
B lymphocytes produce antibodies targeting extracellular pathogens
What is cellular immunity?
T lymphocytes target intracellular pathogens
Where are lymphocytes produced?
T and B Lymphocytes are generated in the bone marrow
Where are T cells located in the body?
T cells mature in the thymus and naive cells circulate in the blood to peripheral lymphoid organs such as lymph nodes, spleen and mucosal tissues
What happens when naive T cells encounter antigens?
If they encounter antigens that they recognise => lymphocyte activation, proliferation & differentiation into effector/memory cells
What are the roles of activated T cells?
Effector T cells => specialised functions
Memory T cells => memory responses (faster, ⇧efficient)
What is MALT?
MALT = mucosa associated lymphoid tissue
Describe the life stages of mature T lymphocytes
Naïve mature T cell => Ag recognition => activation, proliferation and differentiation into: effector T cells & memory T cells => effector function
What is the role of T cells in the immune response?
Designed to fight intracellular microbes
- intracellular bacteria in phagosomes of phagocytes
- viruses: free in cytoplasm of cells (phagocytes or non-
phagocytes e.g. epithelial cells) - cancer cells (mutated proteins from cancer cells)
When do T cells recognise antigens?
T cells recognise antigens only after processing and presentation
What kind of antigens to T cells recognise?
Most T cells (αβ TCR T cells) recognise cell-bound Ags (peptides)
How are antigens processed for T cell recognition?
Peptides from foreign Ags only when bound to major histocompatibility complex (MHC) molecules are recognised by T cells
How do T cells recognise antigens?
T cells recognise antigens via their T cell receptor (TCR)
Describe the structure of TCRs
2 chains: α and β (most common TCR type)
- each chain: 1 variable (V) domain + 1 constant (C) domain
- V and C domains of TCR and BCR are homologous
Where do antigens bind on the TCR structure?
Antigen binding site formed by: Vα + Vβ
The N terminus contains the variable domains α and β which act as the antigen binding site
Which end of the TCR is the constant terminus domain located?
The constant terminus is where the receptor is inserted in the plasma membrane
The transmembrane region is the constant domain
Describe the role of MHC I molecules
MHC I:
- presentation of peptides to CD8+ T cells
- composed of α chain + β2-microglobulin
What is the role of MHC II molecules?
MHC II:
- presentation of peptides to CD4+ T cells
- composed of α chain + β chain
Which cells express MHC I molecules?
MHC I: all nucleated cells
Which cells express MHC II molecules?
MHC II: antigen presenting cells: dendritic cells and macrophages
What are the different types of MHC I molecules in humans?
MHC I: e.g. HLA-A, HLA-B, HLA-C
Outline the different MHC II molecules in humans
MHC II: e.g. HLA-DP, HLA-DQ, HLA-DR
Describe the structure of MHC I molecules
Consists of 2 chains: α and β2m
N terminus domains (α1 and α2) form a groove between each other where antigenic peptide is held for CD8+ TCR presentation
Describe the structure of MHC II molecules
Also consists of 2 chains: α and β2m
N terminus domain structures of MHC II also form a groove for antigenic peptide presentation for CD4 T cells
What are professional APCs?
Cells that specialise in the capture and presentation of antigens (Ag) to CD4+ T cells
Name 2 professional APCs
Dendritic cells => the only APCs capable to present to naïve T cells
Macrophages => present to previously activated effector T cells
Where are dendritic cells found?
Skin, mucosa, tissues
Outline the different functions of dendritic cells
- Capture microbes
- Transport microbes from tissues (e.g. epithelia) to draining lymph nodes
- Process microbes =>Ags
- Present Ags to naïve T cells
- Activate naïve T cells
- Critical in the initiation (priming) of T cell responses
What do Naïve T cells require to be activated?
Naïve T cells need signals in addition to Ag to get activated
Recognition of Ag (peptide:MHC complex) on APC
=> not sufficient to induce T cell activation
What signal occurs to activate Naïve T cells?
B7 ligates to CD28 on naïve T cells
Together with signal 1 => activation of naïve T cells
How does infection effect rate of co-stimulation?
APCs exposed to infection increase the expression of co-stimulatory molecules (B7) and of MHC
Infection increases the antigen presenting function of APCs
What is co-stimulation?
Binding of co-stimulatory molecules (B7 family, e.g. CD80/CD86) on APC by co-stimulatory receptor (CD28) on T cell
What is the result of costimulation?
This co-stimulatory signal drives signalling pathways that promote lymphocyte survival, proliferation and differentiation
What are the roles of macrophages?
=> Phagocytose microbes (e.g. Mycobacteria
tuberculosis)
=> Ag presentation to effector CD4+ T cells (Th1)
=> activation of Th1 cells (see later slides)
=> Th1 cells activate macrophage to kill ingested
microbes
Describe the antigen presentation to CD8+ T cells
All nucleated cells can present peptides derived from proteins from antigens present in the cytosol to CD8+ T cells
Why can all nucleated cells present to CD8+ T cells?
=> all nucleated cells can get infected by viruses
=> all nucleated cells can get cancer-causing mutations
What are the specialised roles of CD8+ T cells?
CD8+ T cells (cytotoxic T cells, CTLs) specialised to:
- recognise viral antigens and mutated proteins
- eliminate cells infected by viruses/malignant cells
How are exogenous pathogens eliminated?
Exogenous Ags (e.g. bacteria) taken up in cells, processed and presented by MHC II to CD4+ T cells Exogenous pathogens (bacteria that grow outside cells)
What are 3 ways antibodies help target exogenous pathogens?
Eliminated by antibodies via neutralisation, opsonisation and complement activation
How do CD4+ T cells aid exogenous pathogen phagocytosis?
CD4+ T cell effectors help macrophages (Th1) and B cells (Th2) to eliminate extracellular bacteria
Outline the process of exogenous pathogen processing and presentation
- Uptake of extracellular proteins into APC vesicles
- Processing of internalised proteins in endosomal / lysosomal vesicles
- Biosynthesis + transport of MHC II molecules to endosomes
- Association of processed peptides with MHC II molecules in vesicles
5, Expression of peptide-MHC complexes on cell surface
How are cytosolic pathogens processed?
Cytosolic Ags (e.g. viruses, mutated proteins in cancer cells) are processed and presented by MHC I to CD8+ T cells
Outline the antigen processing to CD8+ T cells of cytosolic pathogens
- Proteins produced 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
What are cytosolic pathogens?
Pathogens that grow free in the cytosol (viruses) or
Pathogens (bacteria, viruses) that are taken up in phagosomes but are then released into the cytosol
Name the different effector Th cells?
Th (helper) cells: express CD4 (CD4+ T cells)
Th1: help phagocytes to kill ingested microbes
Th2: help eosinophils/mast cells to kill helminths
Th17: role in defense against bacteria & fungi
Tfh (T follicular helper); help B cells (class switch and affinity maturation)
What are the different types of effector T cells?
- Th cells
- Cytotoxic T lymphocytes
- Regulatory T cells
What are the roles of CTL?
Cytotoxic T lymphocytes (CTL):
- express CD8 (CD8+ T cells)
- kill cells infected by microbes that grow free in cytosol
What is the role of regulatory T cells?
Regulatory T cells (CD4+CD25+FOXP3+):
- immune tolerance & inhibition of immune responses
What is the role of cytokines?
Regulates differentiation into different effector T cells
Ensure the right type of effector T cell is generated
Where are cytokines produced?
produced by APCs & other cells in response to infection
Which cytokines induce differentiation into Th1 cells?
IL-12 and IFN-γ
from APC infected with bacteria (e.g. Mycobacteria, Listeria)
What is the main cytokine produced by Th1 cells?
Main cytokine produced by Th1: IFN-γ
What are the roles of Th1 cells?
Main role Th1: activate phagocytes (macrophages)
=> ↑ destruction of intracellular pathogens
Other roles: stimulate production of IgG Abs
=> ↑ phagocytosis of microbes
Describe the process of Th1 differentiation
Naïve CD8+ T cell activated by APC due to bacteria presence
IL-12 and IFN-y drives the differentiation of the activated T cell into Th1
Which cytokines induce differentiation into Th2?
Less well defined (IL-4, IL-25, IL-33)
from APC/cells infected with helminths
What are the main cytokines produced by Th2 cells?
Main cytokines produced by Th2: IL-4, IL-5, IL-13
What is the role of Th2 cells?
Main role Th2: help B cells produce IgE
- IgE => opsonise helminths
- activate eosinophils & mast cells
- eosinophil & mast degranulation and killing of helminths
