Adaptive Immunity Flashcards
Which antigen presentation pathway is used in a viral infection?
MHC1 to CD8+ Tc cells
Which antigen presentation pathway is used in an bacterial/parasitic infection?
MHC2 to CD4+ Th cells
Which cells present antigens via the MHC1 pathway?
all nucleated cells
Which cells present antigens via MHC2 pathway?
Macrophages, Dendritic cells and B cells
Which cell links the innate and adaptive arms of the immune reponse?
Dendritic cells
Where do Dendritic cells go after phagocytosing microbes?
lymph nodes
Where do T cells encounter/interact with DCs?
In lymph nodes
How are T cells positively selected?
T cells enter lymph nodes across HEVs in the cortex
- Non-Ag specific → leave through efferent lymphatics
- Ag-specific → proliferate and differentiate into effector cells
How is the T cell-DC interaction in lymph nodes extended/mediated?
1) Initial contact low affinity:
LFA-1(T cell):ICAM-1(APC)
2) TcR:MHC2 interaction → conformational change of LFA-1 → ↑ affinity → prolong cell-cell contact
What are the 3 signals in T cell activation?
1) Specific signal (Specific TcR→peptide)
2) Co-stimulatory signal (CD28-B7)
3) Cytokines → differentiation
Other than the 3 signals, how else is T cell activation controlled?
Activating and inhibitory receptors
What happens if all 3 signals are not present?
- Only 1: Anergy
- Only 2: no effect
- Only 1 and 2: no differentiation/not effector
What are 3 changes in T cells after activation?
1) ↑ exp. of CTLA-4 → ↓ APC adhesion
2) ↓ exp. of CCR7 & L-selectin → ↓ endothelium adhesion
3) S1P gradient → S1PR-1 receptor on T effector cells → chemotaxis to infection sites
What is CD3?
The signalling component of in T cell membranes common to both CD4+ and CD8+
What are the steps in intracellular signalling in activated T cells upon TcR-MHC binding?
1) CD4/8 recruit ITAMs
2) LCK (kinase) phosphorylate ITAMs
3) LCKs phosphorylate ZAP-70 → downstream signalling → regulate transcription factors
How does IL-2 binding differ in a resting and activated T cell?
Activated T cells have an additional α subunit in the IL-2R (α,ß,y)
→ secrete more IL-2 (+feedback/autocrine loop)
→ clonal expansion
What are CD8+ T cells?
CTLs/Cytotoxic effector cells
How are CD8+ T cells activated?
1)They recognise intracellular pathogens/ peptides displayed on MHC 1
2) Co-stimulation by CD28:B7
3) IL-2 from CD4+ Th cells
Other than signal 1-3, what is needed for fully functional CD8+ T cells responses?
CD40 & 4-1BB exp. on APC (by CD4+ Th cells)
→ co-stimulate CD8+ Tc cells
(by binding to CD-40L and 4-IBBL on T cells respectively)
What are 3 ways in which CD8+ cytotoxic effector cells kill cells?
1) Perforin (forms pore)/Granzymes (activates pro-caspase 3
→ binds to iCAD
→ activate CAD
→ CAD cleaves DNA
→ apoptosis)
2) Fas (on target)/FasL (on CTL)
→ activation of caspase 8
→ mitochondrial swelling
→ cytochrome C egress
→ activation of caspase 3 and CAD
OR
→ activate caspase 9
→ activate caspase 3 and CAD
3) TNF α/ß
→ cross-link surface receptors
→ induce apoptosis
How many subsets do we need to know for which a naive CD4+ T cell can differentiate into?
5
1) Tfh
2) Th1
3) Th2
4) Th17
5) Treg
How are Th1 cells activated/differentiated?
Microbes phagocytosed by Macrophages and DCs → secrete IL-12
→ Il-12 activate NK
→ NK secrete IFN-y
→ Th1 differentiation
What cytokines do Th1 produce?
IFN-y
What cells do Th1 activate?
M1 (proinflammatory) macrophages
What are the functions of M1 macrophages?
1) Proinflammatory (↑MHC, ↑B7)
2) ↑ Microbicidal (↑ ROS and NO, ↑ lysosomal enzymes)
3) Inhibit Th2 (IFN-y)
How are Th2 cells activated/differentiated?
via IL-4 secretion by mast cells, eosinophils, basophils
What cytokines do Th2 produce?
IL-4/13 → IgE class switching
IL-5 → Eosinophil activation
What cells do Th2 activate?
Eosinophils
M2 (anti-inflammatory) macrophages
What are the functions of M2 macrophages?
1) Anti-inflammatory (IL-10, TGF-ß)
2) Wound repair and fibrosis (TGF-ß, Proline polyamines)
What cytokines do Th17 produce?
IL-17 A/F → enhance antimicrobial peptides + recruit neutrophils and monocytes
IL-22 → maintain epithelium
What is the function of Tregs?
Suppress immune response
How to Tregs suppress immune responses?
1) Constitutive expression of CTLA-4 → sequester and down regulate B7 on APC
2) Inhibitory cytokines eg. TGF-ß
3) Metabolic disruption
4) Cytolysis
5) Modulation of DC maturation/function
How to T cells differentiate into memory T cells?
1) one of 3 outcomes when a naive T cells sees and antigen and activates
- Central memory T cell → remain in lymphoid tissue
- Effector memory T cell → remain in peripheral tissues
2) The fate of effector T cells alternative to dying
- Quiescent memory cell w CD45R0)
Other than
1) expressing CCR7 and remaining in lymphoid tissues
2) Differentiating into Effector T cells
Why do memory cells mount a faster response with higher magnitude upon re-infection?
Pre-existing lymphocytes with TcR/BcR/Abs specific for the Ag, ready to undergo clonal expansion
What are 3 reasons for declining T cell responses with age?
1) Thymic involution (↑age → ↓thymic output)
2) Replicative senescence/Hayflick’s limit
3) T cell oligoclonality (↓diversity of T cell repertoire)
What are the 5 types of antibodies?
IgM (1st in infection, Monomer or Pentamer)
IgG (Most abundant, can cross placenta)
IgA (Mucosal)
IgE (Type 1 Hypersensitivity)
IgD (Ag receptor on mature but inactivate B cells, activate mast cell and basophil to produce antimicrobial factors)
What are the functions of IgA?
1) Mucosal immunity (prevent binding of pathogens to mucous membranes)
2) Neutralisation
3) Opsonisation
(also primary Ig in breastmilk and protects baby <2 y/o)
What are the functions of IgE?
1) Mast cell degranulation (has Fc Region specific to Mast cells FcεR1)
2) Anti-parasitic (has variable region specific to allergens and parasite surface antigens)
What are the functions of IgG?
1) Pathogen neutralisation
2) ADCC (FcR or Fcy binding)
What are the functions of IgM?
1) Complement activation (recruit C1)
- low affinity, high avidity
Which Ab(s) mediate complement activation?
IgM
Which Ab(s) mediate immune complex formation?
IgM, IgG
Which Ab(s) mediate opsonisation?
IgG
Which Ab(s) mediate neutralisation?
IgG, IgA
Which Ab(s) mediate ADCC?
IgG
Which Ab(s) mediate mast cell degranulation?
IgE
How does immune complex formation aid in adaptive immunity to pathogens?
IgM and IgG use multi-bi-valent binding sites → formation of large complexes
→ prevent dissemination
→ promote digestion by phagocytotic cells in spleen/liver
How does IgM-mediated complement activation aid in adaptive immunity to pathogens?
IgM recruits complements through the classical pathway
→ C1 binds to Fc region of IgM attached to pathogen
→ initiate complement cascade
→ formation of membrane attack complex (C5-9)
→ cytolysis
How does opsonisation aid in adaptive immunity to pathogens?
IgG coats pathogen and
1) express receptors for FcRs
2) Pro-inflammatory signaling → ultra-aggressive phagocytosis (<10 fold rate of bacterial phagocytosis)
How does neutralisation aid in adaptive immunity to pathogens?
IgG (blood) / IgA (mucosa) bind to pathogen surface/toxins → block binding to receptors (receptor antagonism)
- most effective way to shut down an infection
How does ADCC aid in adaptive immunity to pathogens?
IgG binds to antigen → recruits NK cells with CD16R
→ crosslinking of CD16 → degranulation
→ lytic synapse → apoptosis
What is the difference between affinity and avidity?
Affinity is the strength of binding between 1 paratope and 1 epitope
Avidity is the strength of binding between multiple repeating epitopes on 1 Ag and 1 Ab
How are the light and heavy chains of an antibody held together?
Inter and intrachain disulfide bonds
How is diversity in Abs achieved?
1) Random silencing of LC gene loci (Chromosome 2/22)
2) Random stitching of DNA segments coding for light chains
3) VDJ recombination of heavy chains
4) Somatic hypermutation by AID
5) Cytokine-induced class switching
What is the process of B cell development in the bone marrow?
1) Haematopoietic stem cell → lymphoid progenitor → B cell
2) IgH gene rearrangement → pre-BCR
3) Positive selection for functional VDJ heavy chains (receive +survival signal)
4) IgL gene rearrangment → BCR (IgM)
5) Negative selection for autoreactivity → naive B cells released to circulation
Is B cell isotype switching reversible or irreversible?
Irreversible
Using IgM → IgE as an example, explain the process of B cell isotype switching.
1) Initial μ gene exp. → IgM
2) Th2-B cell interaction → IL-4
3) Looping + excision of μ to y4 (in Ab Fc region) of DNA
4) DNA rearrangement/ligation
5) ε gene exp. → IgE
Where does affinity maturation of B cells occur?
germinal centers of secondary lymphoid organs (eg. lymph nodes)
Explain the process of B cell affinity maturation.
1) Somatic hypermutations via activation-induced deaminase (AID) [DARK ZONE]
→ insert base mismatches (C→U) → multiple potential outcome of repair
→ ↑↑point mutations in variable regions → ↑ variety of affinity
2) Competition for Iccosomes from FDC [LIGHT ZONE]
→ B cells with BCR specific for Ags in Iccosomes
→ bind and tear off iccosome somes → internalise and present via MHC2
3) Activation by CD4+ Th cells/ +ve selection [LIGHT ZONE]
→ Ag:TcR interaction + CD40:CD40L co-stimulation → cytokine secretion
→ cytokine determines B cells differentiation (plasma or memory B cell)
How does the lower dose vaccines and progressive infection produce a stronger immune response?
Later in infection/lower dose → ↓Ag → ↑Competition for Iccosomes
→ only those with ↑ binding affinity have ↑ chance of acquiring iccosomes
→ only B cells with better BcR/Abs can present to Th cells and receive survival/differentiation/proliferation signals
What is the name for a B cell in the dark zone of a germinal center?
Centroblasts (black blasts)
What is the name for a B cell in the light zone of a germinal center?
Centrocytes (cytes, sights, see, light)
