Lecture 14

Question 1

What are myeloid cells?

Answer 1

These are neutrophils, basophils, eosinophils, mast cells and monocytes that become macrophages they possess surface receptors of four key types which recognise fixed antigenic components

Question 2

What are the four major innate receptor types?

Answer 2

Fc Receptors that recognise immune complexes
TLR which recognise a raft of molecular patterns that are unique to micorbes
NK receptors are expressed on NK cells these can be inhibitory or activating and bind a large range of antigens with a large and complex role in immune surveillance
There are also a range of other receptors like Ficolins, Mannose Receptor and NOD like receptors which recognise a range of ligands with the NOD-like receptors being important in regulating the intracellular response to stress
they play a role in chronic inflammatory conditions such as gout and type I diabetes though this is not yet characterized

Question 3

What are the lymphoid cell receptors?

Answer 3

The B cell receptor, T cell receptor (which has both and alpha/beta type and a … type) and the NK-T cell receptor which is found on a small group of T cells which have a very restricted TcR recognising a limited number of microbial peptides presented by non-classical MHC molecules

Question 4

What are Fc Receptors?

Answer 4

These receptors have a variety of forms but they all make use of the Ig-like domain, they bind to the effector (Fc) region of immunoglobulins with low affinity and are only activated when cross-linked by immune complexes
They have intracellular domains that contain ITAM motifs which are phosphorylated and bind and activate tyrosine kinases to initiate signalling
They also play a key role in phagocytosis and engulfment

Question 5

What is the function of Fc(gamma)RI, II, III?

Answer 5

These bind the IgG subtype of antibodies

Question 6

What is the function of Fc(epsilon)R?

Answer 6

This binds the IgE subclass of molecule and are found predominately on mast cells, these are important for dealing with large complex pathogens like parasites which are incapable of being phagocytosed
They trigger the mast cell to release toxic compounds to kill the parasite
However it also plays a role in allergy through type I hypersensitivity where there is an extremely high affinity of IgE immune complexes triggering mast cells in the skin to degranulate releasing histamine and other potent inflammatory models

Question 7

What is the function of Fc(alpha)R?

Answer 7

This binds IgA and is important for mucosal immunity since IgA is important immune secretion in tears, saliva, breast milk and the gut

Question 8

What is the B cell receptor?

Answer 8

This is a receptor expressed on all niave B cells that develop in the bone marrow, it is a membrane bound IgM molecule with each B cell having its own unique receptor as aresult of stochastic gene rearrangement
It exists as a surface coplex with Igalpha and Igbeta molecules that posses ITAM motifs
Activation requires crosslinking of BcR by multivalent antigen this binds the syk kinase which initiates a phosphorylation cascade of the ITAMs on the intracellular domains of the Igalpha and Igbeta molecules
It is also present as part of a larger complex of CD19, TAPA and CD21 which are also essential to effective signalling

Question 9

What functions are the T cell receptors responsible for?

Answer 9

Direct killing of virally infected cells
Regulation of antibody production through cytokine help
Regulation of isotype class switching
Regulation of macrophage mediated killing
Natural killer activity

Question 10

What are the functional subsets of T cells?

Answer 10

There are CD8 cytotoxic T cells which are restricted by MHC class I, these contain granules loaded with perforin to form pores in target cell membranes and the protease ganzyme B which is injected into these cells to induce apoptosis
There are also CD4 T helper cells which are restricted by MHC class II, they produce interleukins essential for both T cell and B cell function growth making them the true drivers of the immune system, they can be further divided into TH1, TH2, TH17 and Treg subtypes

Question 11

What are the functions of TH1 cells?

Answer 11

These cells promote cellular immunity producing lots of interferon gamma and IL-2 driving the growth of T cells and enhancing the ability of CD8 T cells to kill virally infected cells

Question 12

What are the functions of TH2 cells?

Answer 12

These promote a strong humoral B cell antibody response with production of large amounts of IL-4 and very little INFgamma or IL-2 this response is better for extracellular pathogens such as bacteria

Question 13

What are the functions of Treg cells?

Answer 13

These are potent suppressor cells producing large amounts of IL-10 and TGF-Beta, these are essential to control the immune response and prevent a damaging inflammatory reaction or an autoimmune condition

Question 14

What are the functions of TH17 cells?

Answer 14

These are a very important proinflammatory T cells thought to be important in the propagation of autoimmune disease they produce lots of IL-6, IL-17 and IL-21
They are thought to be important in driving or enhancing the innate response by myeloid cells

Question 15

What is the role of polarisation of the immune response?

Answer 15

An immune response to an antigen will typically require some form of balance of the 4 TH cell subsets with polarisation being very rare and implicated as having a role in inappropriate responses causing conditions such as asthma where a strong TH2/TH17 has developed with insufficient Treg development

Question 16

What are NK-T cells?

Answer 16

These are small but powerful group of T cells which have a very restricted alpha/beta TcR that recognizes compounds presented by the non-polymorphic MHC molecule CD1 they produce a large amount of cytokines so far the only a single ligand has been identified called alpha glactosyl ceramide form a marine sponge
These cells are necessary for a response to certain unique pathogens

Question 17

How does T cell repertoire selection occur in the thymus?

Answer 17

There is an elaborate mechanism which occurs in the thymus and is referred to as positive and negative selection prior to and after birth where cells that respond too strongly or not at all to MHC are deleted leading to only cells which recognize MHC within a narrow window of affinity being selected

Question 18

What are the two types of TcR?

Answer 18

These are Tcr that are coded for by separate genetic loci
There is the alpha/beta TcR which recognizes classical MHC molecules and is composed of two glycosylated chains (alpha and beta) which both have transmembrane domains
There is also the gamma/delta TcR which often recognise microbial antigens presented in thr MHC-like CD1 molecules with some not being MHC restricted at all

Question 19

What are the features of the TcR beta chain?

Answer 19

This is most similar to the IgH in B cells where it has two Ig-like domains, Cbeta and Vbeta, the variable domain creates the antigen binding surface with the C domain is constant in all cells

Question 20

What are the features of the TcR alpha chain?

Answer 20

This is most similar to the IgL chain in B cells, it has two Ig-like domains C alpha nd V alpha

Question 21

What are the features of TcR gene rearrangement?

Answer 21

This follows the same process as Ig
However in the case of TcR the beta-chain region is under strict allelic exclusion while the alpha chain does not so two forms of alpha chain may be found in one T cell
The beta chain also rearranges first

Question 22

What are the features of the TcR gamma chain?

Answer 22

This contains two Ig like domains V gamma and Cgamma
The C regions have transmembrane regions with charged amino acids and sometimes has a disulphide bond linking to the zeta chain though this chain can also form homodimers
While this chain has the ability to generate great diversity, only a very restricted repertoire is expressed in the periphery

Question 23

What are the features of the TcR-delta chain?

Answer 23

This is constructed from two Ig-like domains with a single Cdelta region having a charged transmembrane region
The is chain has V,D,J and C segments allowing for the ability to generate huge diversity in the junctional region however the peripheral repertoire of these T cells is very limited

Question 24

What suggests that the gamma-delta TcR may be an earlier form of TcR?

Answer 24

Rearrangement of these genes occurs earlier in thymic development suggesting this is an earlier version of TcR that has been superseded by the alpha-beta TcR

Question 25

Why are some gamma-delta T cells not restricted?

Answer 25

Some of the T cells with this receptor recognize antigen directly in the absence of MHC molecules such as lipoarabinomannan which is a complex bacterial lipopolysaccharide recognised by Vgamma9
Other ligands include heat shock proteins

Question 26

Why are gamma-delta TcRs important in mycobacteria infection?

Answer 26

Mouse knockouts of these die when challenged with mycobacterial infections

Question 27

What is the role of the CD3 components of the TcR complex?

Answer 27

The alpha and beta chains of TcR do not themselves for activation signals to the T cell, instead the associated CD3 chains perform this function

Question 28

What is the function of CD3 gamma?

Answer 28

This is a type 1 membrane protein with a short cytoplasmic domain, it has a charge in its transmembrane domain with forms a salt bridge with the oppositely charged alpha chain, it contains ITAM sequences in the cytoplasmic domain

Question 29

What is the function of CD3 epsilon?

Answer 29

An Ig-like protein with a short cytoplasmic tail and –ve charge in its transmembrane domain, there is one ITAM in the cytoplasmic domain

Question 30

What is the function of CD3 delta?

Answer 30

Another Ig-like protein with a short cytoplasmic domain containing an ITAM

Question 31

What is the function of CD3 zeta?

Answer 31

This is the most important CD3 chain for T cell activation, it is found as a dimer in most cells and unlike the other CD3 chains its cytoplasmic domain has 3 ITAMs whaich are essential for binding associated tyrosine kinases
Cells without these chains have no activation potential

Question 32

What is an ITAM?

Answer 32

This stands for an immunoglobulin tyrosine-based activation motif, it is a conserved region containing a tyrosine which when phosphorylated binds cytosolic protein tyrosine kinases via their SH2 domains

Question 33

What is an ITIM?

Answer 33

Immunoglobulin tyrosine-based inhibitory motif, this binds SHP-1 domain containing phosphatases leading to the dephosphorylation of adaptor molecules

Question 34

How does CD4 play a role in T cell activation?

Answer 34

This molecule has a low affinity binding site to the beta 2 region of MHC class II as well as a tyrosine kinase call p56lck which is constitutively associated with the cytoplasmic domain of CD4, this initiates the phosphorylation of the CD3 chains when the two are brought together in close proximity through surface clustering

Question 35

How does CD8 play a role in T cell activation?

Answer 35

This forms a dimer on the surface of T cells causing it to have a weak affinity of the alpha3 domain of MHC class I it has a cytoplasmic tail which is linked to p56lck

Question 36

What are NK cells?

Answer 36

These are large granular lymphoid cells that selectively kill cells which do not express any MHC class
They have an identical mechanism of cell killing to that used by CD8 cells (perforins and granzymes)
They are innate receptors which recognise invariant ligands and are two discrete types, activating and inhibitory
They are believe to function in foetal/placental immunity

Question 37

What are the inhibitory receptors on NK cells?

Answer 37

There is a large family of killer inhibitory receptors which are Ig like glycoproteins that sense the presence of polymorphic and non-polymorphic MHC
Most of these are inhibitory receptors containing an ITIM domain in their cytoplasmic domains blocking cell activation and cytolysis (the default path of NK cells)

Question 38

What are the activating receptors on NK cells?

Answer 38

A few NK receptors have ITAM motifs on their cytoplasmic domain this includes KIR2DS in humans which recognizes the cell surface ligand MICA which indicates the cell has become stressed and is no longer viable