Flashcards in Lecture 14 Deck (38):
What are myeloid cells?
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
What are the four major innate receptor types?
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
What are the lymphoid cell receptors?
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
What are Fc Receptors?
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
What is the function of Fc(gamma)RI, II, III?
These bind the IgG subtype of antibodies
What is the function of Fc(epsilon)R?
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
What is the function of Fc(alpha)R?
This binds IgA and is important for mucosal immunity since IgA is important immune secretion in tears, saliva, breast milk and the gut
What is the B cell receptor?
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
What functions are the T cell receptors responsible for?
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
What are the functional subsets of T cells?
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
What are the functions of TH1 cells?
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
What are the functions of TH2 cells?
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
What are the functions of Treg cells?
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
What are the functions of TH17 cells?
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
What is the role of polarisation of the immune response?
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
What are NK-T cells?
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
How does T cell repertoire selection occur in the thymus?
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
What are the two types of TcR?
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
What are the features of the TcR beta chain?
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
What are the features of the TcR alpha chain?
This is most similar to the IgL chain in B cells, it has two Ig-like domains C alpha nd V alpha
What are the features of TcR gene rearrangement?
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
What are the features of the TcR gamma chain?
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
What are the features of the TcR-delta chain?
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
What suggests that the gamma-delta TcR may be an earlier form of TcR?
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
Why are some gamma-delta T cells not restricted?
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
Why are gamma-delta TcRs important in mycobacteria infection?
Mouse knockouts of these die when challenged with mycobacterial infections
What is the role of the CD3 components of the TcR complex?
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
What is the function of CD3 gamma?
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
What is the function of CD3 epsilon?
An Ig-like protein with a short cytoplasmic tail and –ve charge in its transmembrane domain, there is one ITAM in the cytoplasmic domain
What is the function of CD3 delta?
Another Ig-like protein with a short cytoplasmic domain containing an ITAM
What is the function of CD3 zeta?
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
What is an ITAM?
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
What is an ITIM?
Immunoglobulin tyrosine-based inhibitory motif, this binds SHP-1 domain containing phosphatases leading to the dephosphorylation of adaptor molecules
How does CD4 play a role in T cell activation?
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
How does CD8 play a role in T cell activation?
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
What are NK cells?
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
What are the inhibitory receptors on NK cells?
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)