T Cell Activation & Generation of Effector T Cells Flashcards
The life stages of T lymphocytes
Generated in bone marrow => undergo maturation in thymus
Mature naïve T cells released from thymus into the blood
Recirculate between blood and peripheral lymphoid organs (lymph nodes, spleen, MALT)
If they encounter antigens that they recognise => lymphocyte activation, proliferation & differentiation into effector/memory cells
Effector T cells => specialised functions
Memory T cells => memory responses (faster, ⇧efficient)
T cell role
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: do not recognise antigens directly
T cells: recognise antigens only after processing and presentation
Most T cells (αβ TCR T cells) recognise what
=> T cells recognise cell-bound Ags (peptides)
=> peptides from foreign Ags only when bound to major histocompatibility complex (MHC) molecules
Other subsets of T cells recognise what
Other subsets of T cells (γδ T cells recognise antigens that are not peptides
Describe structure of T cell receptor
=> 2 chains: α and β (most common TCR type)
γ and δ (TCR in γδ T cells)
- each chain: 1 variable (V) domain + 1 constant (C) domain
Antigen binding site formed by: Vα + Vβ
- V and C domains of TCR and BCR are homologous
MHC molecules display peptides from processed Ag - compare types
MHC I: presentation of peptides to CD8+ T cells
composed of α chain + β2-microglobulin
MHC II: presentation of peptides to CD4+ T cells
composed of α chain + β chain
γδ T cells recognise antigens that are what
γδ T cells recognise antigens that are not displayed by MHC I and MHC II (are not MHC restricted)
Expression of MHC molecules - compare types
MHC I: all nucleated cells
MHC II: antigen presenting cells: dendritic cells
macrophages
Human MHC molecules = HLA (human leucocyte Ags) - list all with MHC I/II
MHC I: e.g. HLA-A, HLA-B, HLA-C
MHC II: e.g. HLA-DP, HLA-DQ, HLA-DR
Antigen presenting cells (APC) - define
Cells that specialise in the capture and presentation of antigens (Ag) to CD4+ T cells
Professional APCs - give examples and describe roles
Dendritic cells => the only APCs capable to present to naïve T cells
Macrophages => present to previously activated effector T cells
CD8+ T cells - function
CD8+ T cells recognise Ags displayed by nucleated cells (not just APC but also cells that are not APCs)
Dendritic cells - distribution + function
skin, mucosa, tissues
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
Naïve T cells need what for activation
Naïve T cells need signals in addition to Ag to get activated
Explain importance for combination of signals 1 and 2
Signal 1: recognition of Ag (peptide:MHC complex) on APC
=> not sufficient to induce T cell activation
=> without signal 2 => no response or anergy of T cell
Signal 2: co-stimulation - describe
=> binding of co-stimulatory molecules (B7 family, e.g. CD80/CD86) on APC by co-stimulatory receptor (CD28) on T cell
=> together with signal 1 => activation of naïve T cells
Signal 2: co-stimulation - effect on APCs
=> APCs exposed to infection increase the expression of co-stimulatory molecules (B7) and of MHC
Infection increases the antigen presenting function of APCs
Signal 3: cytokines produced by APCs (after infection) - functions
=> regulate the differentiation of activated T cells into different types of effector T cells
e. g. IL-12 and IFN-γ from APC => differentiation into Th1
e. g. IL-4 from APC => differentiation into Th2
=> ensure the right type of effector T cell is generated
e.g. effector T cell type that is most suited to respond to the infection that triggered the response
Th1 <=> macrophage co-operation
Th2 <=> B cell and eosinophils / mast cell co-operation
Macrophages - functions
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
Antigen presentation to CD8+ T cells - which cells can do this
All nucleated cells can present peptides derived from proteins from antigens present in the cytosol to CD8+ T cells
Nucleated cells can be affected by what
=> all nucleated cells can get infected by viruses
=> all nucleated cells can get cancer-causing mutations
=> CD8+ T cells (cytotoxic T cells, CTLs) specialised to:
- recognise viral antigens and mutated proteins
- eliminate cells infected by viruses/malignant cells
Exogenous Ags - describe processing
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)
=> taken up by phagocytes
=> eliminated via killing in phagocytes
=> eliminated by antibodies (via neutralisation, opsonisation and complement activation)
CD4+ T cell effectors - function
CD4+ T cell effectors help macrophages (Th1) and B cells (Th2) to eliminate extracellular bacteria
Treatment of pathogens in cytosol
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
=> efficiently eliminated via killing by CD8+ T cells (CTLs)
CD8+ T cells specialised to do what
CD8+ T cells specialised to eliminate cells infected by viruses and cancer cells
Th (helper) cells: function
Th (helper) cells: express CD4 (CD4+ T cells)
Th1: function
Th2: help eosinophils/mast cells to kill helminths
Th17: function
Th17: role in defense against bacteria & fungi
Tfh (T follicular helper); function
Tfh (T follicular helper); help B cells (class switch and affinity maturation)
Cytotoxic T lymphocytes (CTL): function
Cytotoxic T lymphocytes (CTL):
express CD8 (CD8+ T cells)
kill cells infected by microbes that grow free in cytosol
Regulatory T cells (CD4+CD25+FOXP3+): function
Regulatory T cells (CD4+CD25+FOXP3+):
immune tolerance & inhibition of immune responses
Signal 3: cytokines - produced by what and regulates what
Signal 3: cytokines
=> produced by APCs & other cells in response to infection
=> regulate the differentiation of activated T cells into different types of effector T cells
=> ensure the right type of effector T cell is generated
e.g. effector T cell type that is most suited to respond and help eliminate the infection that triggered the response
Cytokines that induce differentiation into Th1
Cytokines that induce differentiation into Th1
IL-12 and IFN-γ
from APC infected with bacteria (e.g. Mycobacteria, Listeria)
Main cytokine produced by Th1
Main cytokine produced by Th1: IFN-γ
Th1 - functions
Main role Th1: activate phagocytes (macrophages)
=> ↑ destruction of intracellular pathogens
Other roles: stimulate production of IgG Abs
=> ↑ phagocytosis of microbes
Cytokines that induce differentiation into Th2
Less well defined (IL-4, IL-25, IL-33)
from APC/cells infected with helminths
Main cytokines produced by Th2:
Main cytokines produced by Th2: IL-4, IL-5, IL-13
Main role Th2:
Main role Th2: help B cells produce IgE
- IgE => opsonise helminths
- activate eosinophils & mast cells
- eosinophil & mast degranulation and killing of helminths
CD4+ T cell responses
Naïve T cells recognise Ags in peripheral lymphoid organs
Activation, proliferation, differentiation into effectors
Effector T cells leave activation site (PLO) via blood
Effector T cell migration to site of Ag entry
Effector T cells perform their effector functions to eliminate Ag together with other cells (macrophages, B cells, etc.)
CD8+ effector T cells=cytotoxic T lymphocytes (CTL) - functions
Ag recognition by naïve CD8+ T cells in PLOs
activation, proliferation, differentiation into effectors
Effector CD8+ T cells leave activation site (PLO) via blood
Effector CD8+ T cell migration to site of Ag entry
Effector CD8+ T cells perform their effector functions to eliminate Ag/infection
CD8+ T cells (cytotoxic T cells, CTLs) specialised to:
- recognise viral antigens and mutated proteins
- eliminate cells infected by viruses/malignant cells
CD8+ T cells (cytotoxic T cells, CTLs) - main mech
Main mechanism: kill infected cells
Killing is antigen-specific and contact-dependent
CD8+ T cells (cytotoxic T cells, CTLs) - effect on healthy/unhealthy cells
Uninfected/healthy cells are not killed by CTLs!
Killing of infected cells by CTL => eliminates reservoirs of infection
CD8+ T cells (cytotoxic T cells, CTLs) - mediated by
Killing mediated by cytolytic molecules:
Perforin: forms pores => delivery of granzymes
Granzymes A, B, C: initiate apoptosis
delivered at the site of contact between CTL:target !
=> prevents killing of neighbouring healthy cells
Killing mediated by death receptor pathway (Fas/FasL)
