L8. Role of MHC proteins Flashcards
What are all the parts needed for T cell activation?
For T cell activation, in addition to the TCR complex (αβ (T cell receptor) +CD3 + zeta chain), co-receptors are also required (on T cell and antigen presenting cells- CD4 and CD8).
Why are co-receptors (CD4 and CD8) required for T cell activation?
1) stabilise the interaction
2) facilitate signalling
How do CD4 and CD8 interact with MHC proteins and TCRs?
1) CD4/CD8 interact with invariant regions on MHC II/I at their non-polymorphic domains
2) CD4 and CD8 act as co-receptors for the TCR complex. Both contain Ig-like domains.
What is the interaction for 1) T Helper cells 2) Cytotoxic T cells?
1) MHCII + antigen <–> CD4 is the coreceptor on T Helper cell
>CD4 acts on MHCII by the non-polymorphic regions.
2) MHCI + antigen <–> CD8 coreceptor on cytotoxic T cell
>CD8 can act on the non-polymorphic regions of MHCI.
How do CD4/8 adaptor proteins promote T cell activation?
> The C terminus of CD4/8 protein has a protein kinase (called Lck) associated
> Upon co-receptor engagement of the TCR with antigen:MHC, Lck phosphorylates the ITAMs onthe CD3 (ITAMS on delta, gamma, and two epsilon subunits so four overall) and zelta (three ITAMS) ITAMs.
What is thymic selection and what is its purpose?
After T cell from bone marrow enters thymus, undergoes rearrangement of T cell receptor genes (αβ or γδ), Very strict selection occurs, so T cell only bares a receptor that recognises self MHC and doesn’t react against self-molecules.
How are T cells selected in thymic selection in 3 steps
1) Rearrangement of T cell receptor genes, making T cell receptor
2) Positive selection, T cell receptor has to bind to self-MHC very well (otherwise can’t recognise antigen)
>Apoptosis to T cells which fail
>Only occurs for T cells expressing alpha, beta chains, as gamma delta ones don’t require antigen presentationvia MHC
3) Negative selection, any T cells with receptor that binds to self-peptides is also selected against
>T cells undergo apoptosis if recognise/ react to self
In theory why should thymic selection not work?
Thymus is a tissue, might not express proteins found in the rest of the body like insulin, how does it train T cells to not attack these proteins
How does the thymus get around the issue of normal tissue not expressing all proteins found in the body?
Gene is switched on in the thymus, AIRE facilitates the expression of a wide array of tissue-specific antigens (TSAs) not normally found there: AIRE (autoimmune regulator) allows expression of non-thymus proteins, allowing for negative selection of T cells for these proteins (gene also found in secondary lymphoid tissue).
What happens to people without AIRE (autoimmune regulator)?
People without these genes have autoimmune disease greater chances
What are the 3 gene loci for a) MCHI b) MCHII on chromosome 6?
a) MHCI genes have 3 gene loci, HLA-A,B, C
>Each encoding for a polymorphic alpha gene (at distal end)
b) MHCII genes have 3 gene loci, HLA-DP, DQ, DR
>Each encodes for an alpha chain and beta chain polymorphism.
>Very polymorphic (many allele variants), very polymorphic e.g. HLA-B has ~5000 alleles
What are the HLA genes encoded by and what does this mean?
> Encoded by the Major Histocompatibility gene Complex (MHC)
> When I say that “The Major Histocompatibility Complex (MHC) encodes for both MHC class I and class II molecules,” it means that the MHC is a specific region of the genome (located on chromosome 6 in humans) that contains the genes responsible for producing the proteins that make up MHC class I and class II molecules.
How is diversity generated for MHC proteins and what is the effect of this?
> These are inherited from parents (usually different genes then), co-dominant expression (i.e. both alleles inherited from each parent expressed on cells)
> This increases the number of MHC proteins found on cells, so can bind to winder range of peptides.
What is the difference between MHC diversity and B and T cell receptor diversity?
MHC diversity is inherited and small compared to that of B and T cell receptors
Where does most variation occur in the structure of an MHC protein?
Allelic variation occurs predominantly in the peptide-binding regions (All variation Is in the areas that bind peptides).
What are 3 big consequences of MHC polymorphism?
1) Skin graft rejection.
2) Ensures wide recognition of foreign peptides (as MHC are very polymorphic)
3) As MHC polymorphism evolved in response to pathogens diseases have influenced the MHC proteins we express.
>Humans are very polymorphic but some species have restricted polymorphisms but tend to be solitary species.
What is the issue with the MHC polymorphism only coming from inherited genes and no recombination?
> Variability of MHC molecules is small compared to that of TCR (as is all inherited in genome)
1) T cell responses determined by an individual’s MHC type on surface of cells, as can’t respond to peptides the MHC protein hasn’t processed (limited by MHC diversity).
2) As each MHC allele can bind a restricted range of related peptides so for In inbred people, some can’t respond to certain antigens as their MHC proteins don’t have enough variability, so we need MHC polymorphism
3) Responders and Non-responders
Overall what are the 5 roles of MHC proteins?
1) Graft rejection
2) Antigen presentation to T cells
3) T cell activation development of T cell repertoire/tolerance in thymus
4) Self/non-self recognition (NK cells “detect” alterations MHCI)
5) Expression of certain MHC genes may cause association with certain autoimmune diseases (shown in table)
How could MHC proteins effect our choice of mate?
> Want to mate with someone with different MHC proteins as would increase the range of pathogens the MHC proteins can respond to.
> Study which suggested that can detect which MHC proteins an individual is expressing through sense of smell (females found T shirts with distinct MHC proteins more attractive)
What is a positive effect of MHC proteins allowing recognition of self/ non-self in the immune response?
NK cells are programmed to kill unless detect self-MHCI on surface of cell, some viruses will downregulate MHCI to avoid cytotoxic T cells to try avoid cytotoxic T cells but are now vulnerable to be killed by NK cells.
Describe the 1) Antigen-Independent 2) Antigen-Dependent steps in antibody development
1) ANTIGEN-INDEPENDENT (bone marrow)
>Acquire B cell receptors in bone marrow
>Antibody genes undergo rearrangement; “naïve” B cells expressing membrane IgM +/- IgD are generated.
2) ANTIGEN-DEPENDENT (2ndry lymphoid tissue): out in the body
>B cells activated by antigen (recgonised by B cell receptor) divide and differentiate into plasma cells (clonal selection) secreting soluble antibody.
>Affinity maturation (somatic hypermutation) and class switching may also occur by AID gene which causes mutations.
What mediates humoral immunity?
Soluble antibodies
What are the 5 heavy chain classes of Immunoglobulins, what is their symbol and what are their functions?
1) IgG (γ)
>Main class in serum and tissues important in secondary responses (encountering pathogen for second time)
2) IgM (μ)
>Important in primary responses (always made first when come across a pathogen and when immune system is developing).
3) IgA (α)
>In serum & secretions protects mucosal surfaces (in tears, mucus, milk; most infections occur in mucosal surfaces)
4) IgD (δ)
>?
5) IgE (ε)
>Present at very low levels involved in protection against parasites and allergy
What is the purpose of having different heavy chain classes of antibody, and give an example of this use.
> Antibodies of different classes act in distinct locations and have distinct effector functions
> E.g. IgM good at first, then to specialise against pathogen, e.g. pathogens in tissues express IgE to get into tissue.
Describe the domain nomenclature of an Immunoglobulin G (γ chain)?
> Variable regions are VL or VH (light or heavy chain) at distal ends.
> Constant are CL (light chain at start of Fab arm), CH1, CH2, CH3 domains (last three are heavy chains, 1 is on Fab arm, 2/3 on Fc region)
What are two unique properties to IgG?
> IgG has large hinge region
> 2 carbohydrate molecules keeps CH2 domains slightly apart, normally the domains pair together with non-covalent interactions (functions of carbohydrates).This alters the Fc region shape so also alters the effector functions of IgG
What is the main role of carbohydrates in antibodies?
Carbohydrate allowing antibody to be soluble, can also be important for function
What does IgG always occur as, where is it found and what is its role?
> Always occurs as monomer, m.wt 150,000
> main antibody in tissues and blood
> important in secondary or “memory” responses
Describe the 1) Primary Immune Response 2) Secondary Immune Response?
1) Primary response:
>First place, IgM is always made in primary response (rise after first infection)
>Few days later, B cells switch class to IgG (primary antigen response)
2) If antigen returns again causes secondary response
>IgM is produced much quicker with the same level of concentration
>IgG is created much quicker than in primary and to a much higher level in serum, can be IgA and IgE too.
What is AID required for?
AID is required for class switching and affinity maturation
