Lecture 10 & 11 MHC-HLA Structure, Function & Genes APM Flashcards
what are major histocompatibility complex (MHC)?
cluster of genes located on a single chromosome coding cell-surface molecules that present antigen to T cells and immune proteins
MHC is found on chromosome ___ in humans and chromosome ___ in mice
6; 17
MHC present antigen to ___ cells and engage ___ cells
T; NK
MHC is also celled ____ in humans and ___ in mice
human leukocyte antigens (HLA); H2 complex
what are the classes of MHC?
I, II, and III
does class III MHC present antigen?
no
what is the function of MHC 3?
encode relatively conserved immune mediators that are important for inflammatory responses
what are the 2 functions of MHC1?
- present intracellular antigens to CD8+ T cells
2. engage NK cells for self/missing self discrimination
where are MHC1 found (on what cells?)
nearly all nucleated cells
what is the structure of MHC1?
one large glycoprotein (alpha chain with 3 extracellular domains –a1, a2, a3) and one small protein light chain
what are the variable regions of the MHC1?
- a1 and a2 domains form a cavity (2 extended a helices on a B-pleated sheet)
- the cavity is called the antigen binding groove and the linear peptide sits inside
- peptide anchor residues are at each end
what are the conserved regions of the MHC 1?
- transmembrane domain
- a3 domain
- B2m (beta-2-microglobulin)
what is the transmembrane domain in MHC1?
consists of 3 regions: external, a hydrophobic sequence (membrane anchor), and a short hydrophilic sequence (cytoplasmic)
what is the a2 domain of the MHC1?
highly conserved and noncovalently interacts with B2-microglobulin, as well as with the CD8 co-receptor on cytotoxic T cells
what is the B2m (Beta-2-microglobulin) of the MHC1?
highly conserved; interacts with a3 domain and stabilizes MHC1 complexes
what is the function of the MHC2?
present antigens derived from extracellular/exogenous compartment to CD4+ T cells
on what cells can you find MHC2?
professional APC (DCs, macrophages, B cells)
explain the structure of MHC2
- 2 different glycoprotein chains (a-33kDa and B-28kDa) and are subdivided by their extracellular regions: 1 & 2
- a and B chains are organized into 2 external globular domains, a hydrophobic membrane anchor, and a short hydrophilic cytoplasmic tail
what are the 3 variable regions of the MHC2?
- a1 & B1 form the antigen/peptide-binding groove
- peptides are 13-18 AA long and hang off the end
- peptide anchor residues are distributed across the length of the antigen binding groove
what are the conserved regions of the MHC2?
a2 and B2 are relatively conserved between MHC2 molecules
what is the most polymorphic gene in the human genome?
MHC
____ gene products are responsible for transplantation rejection reactions
histocompatibility
the specific set of MHC molecules expressed by an individual will influence the repertoire of ___ to which the individuals T cells can respond
antigens
MHC ___ denotes the set of allelic forms of MHC1&2 genes expressed by a particular strain of mice or person
haplotypes
____ is rare, so groups of MHC genes are inherited together
meiotoc recombination
why is meiotic recombination rare in MHC genes?
the genes are in high linkage disequilibrium
in mice the haplotype is designated by a ____
arbitrary superscript e.g. H-2a
in humans, haplotypes are named for the ___ they contain
genes
different MHC genes are named for their ___
locus
differences between alleles are typically found at the ___MHC1 regions and ___MHC2 regions
a1 & a2; a1 & B1
what is the function of polymorphisms in MHC?
allows diversity in terms of what peptides can be presented and the interactions between peptides + MHC with T cell receptors
how does polymorphic diversity make it more challenging for pathogens to evade recognition?
polymorphic diversity makes it more likely that someone in a population can mount an immune response
which MHC gene is the most diverse?
Class 1 HLA locus B
peptide contact with class 1 MHC is by ____ bonding
hydrogen
t/f in class 1 MHC, longer peptides bulge in the middle whereas shorter peptides lie flat in the groove
t
what residues determine which peptides can bind?
variable anchor residues
co-dominant expression ___ (increases or decreases) the likelihood of antigen presentation
increases
t/f MHC establishes diversity even among closely related people
t
how can a reduction in MHC polymorphism may predispose a species to Dx?
by limiting the range of processed antigen that can interact with MHC molecules
give an example of an animal that does not have enough MHC diversity and therefore experiences more contagious cancer
tasmanian devils
variations in antigen presentation by different MHC alleles may determine the effectiveness of the _____ to a given pathogen
immune response
why is it advantageous to have high level polymorphisms of MHC?
it provides a broad range of antigen-presenting MHC molecules
t/f some autoimmune Dx and certain Dx caused by pathogenic organisms are associated with particular MHC alleles
t
what are the 2 models that explain the MCH2 and immune responsiveness?
- determinant selection model
2. holes in the repertoire model
explain the determinant selection model
different allelic forms of class 2 MHC molecules differe in their ability to bind and present processed antigen. This means different people with different haplotypes will have different abilities to bind and respond to peptides from pathogens
explain the holes in the repertoire model
states the T cells bearing TCR that recognize foreign antigens that closely resemble self-antigens are absent, having been eliminated during thymic development. This means there will be peptides for which there are no T cells to respond in the repertoire
why may both the determinant selection model and the holes in the repertoire model be true?
BC you need three things to line up to generate a TCR+MHC+peptide complex and loss of any one of these would impair responsiveness
HIV induces ____(upregulation or downregulation) of HLA expression
downregulation
cytomegalovirus infection interferes with ___ expression
B2m
adenovirus interferes with TAP1 and TAP2, which prevents ____
antigen loading
what are NK cells?
cytotoxic and cytokine-producing effector cells
NK cells arise from the common lymphoid progenitor and are most closely related to ___ cells
T
development of NK cells happens almost independently of the ____
thymus
what are 3 common NK cell markers?
- CD56 (human)
- NK1.1 (some mice)
- DX5 (all mice)
is target cell recognition by NK cells MHC-restricted?
No, but some NK cells appear to exhibit immunologic memory
NK cells are an important source of ___ which increases the microbial activity of macrophages and impacts adaptive immunity by promoting Th1 differentiation, inhibiting Th2 development and driving CTL development
IFN-y
what are 2 modes of NK cell-mediated killing?
- granule-dependent killing
2. killing by death ligands
explain the granule-dependent killing by NK cells
NK cells are activated to polarize granules toward the target cell; uses perforin to make wholes in the membrane and granzyme B to induce cell death
explain killing by death ligands by NK cells
NK Fas ligand binds to the Fas on the target cells and trail receptors of NK cell bind to TRAIL on the target cell
in both granule-dependent killing and killing by death ligands, death is by _____
apoptosis (programmed cell death)
explain apoptosis
a quiet form of cell death that packages up intracellular contents into “bite-size” pieces for phagocytes to engulf and safely recycle
apoptosis prevents ___
autoimmunity or responses to intracellular features
apoptosis can be induced by the ___
immune system
what type of cell death is a normal part of cell turnover?
apoptosis
necrosis is also known as ____ death
messy cell
explain necrosis
cell death by uncontrolled means (i.e. injury, infections/lysis, granzyme B). Cell contents are released nto the environment and immune responses may be mounted against them
what are 3 ways NK cells can be activated?
- By cytokines
- by binding to receptors
- by binding to antibodies bound with targets
what cytokines can activate NK cells to increse their lytic activity against virus-infected cells?
Type 1 IFNs (IFN-a and IFN-B)
what receptors can NK cells bind to in order to become activated?
- C-type lectin receptors (i.e. NKG2C, NKG2D, activating Ly49)
- Immunoglobulin familiy members (i.e. NCRs activating KIR)
when NK cells are activated by binding to antibodies bound with targets, it is called ____
antibody-dependent cell-mediated cytotoxicity
antibody-dependent cell-mediated cytotoxicity of NK cells works best with which antibody?
IgG
binding to what receptors can lead to the inhibition of NK cells?
c-type lectin receptors (i.e. NKG2A, NKG2E, inhibitory Ly49)
Immunoglobulin family members (i.e. inhibitory KIR)
t/f NK cells are activated when the incoming signals for activation outweigh the incoming signals for inhibition
t
virus infection can induce ____ (downregulation or upregulation) of MHC
downregulation
target cells with ____levels of MHC1 are killed by NK cells and those with ___ levels are not killed
low; normal
when would a target cell expressing normal levels of MHC1 be killed by NK cells?
if they express a surplus of activating signals
to NK cells, MHC/HLA signal that a cell is ___ and ____, so binding of MHC/HLA to NK cells _____ them (inhibitis or activates)
healthy and self; inhibit
why does inflammation cause NK cells to be activated?
there is a loss of MHC/HLA to signal to the NK cells that they are self cells
the ____ which bind HLA and mediate missing self recognition are the 2nd most polymorphic
killer immunoglobulin-like receptors (KIR)
what must an NK cell recognize on a cell to see it as “self”?
the cell must have the same “self” HLA that the NK cell has been trained to see (needs to be a specific HLA, not just that an HLA is present)
in mice, MHC interacts with ___ receptors for NK cell education
Ly49
explain how T and NK cell mediated cytotoxicity are complementary
If an MHC presents a peptide that indicates damage, a T cell will kill the target cell
If MHC is downregulated to avoid detection by T cells, NK cells will kill it
class 1 MHC are found on what cells?
all nucleated cells
class 2 MHC are found on which cells?
professional APC (dendritic cells, macrophages, B cells(
the expression of MHC 1&2 genes is regulated by transcriptional factors and controlled by promotor regions in the _____ region
5’ untranslated region (UTR)
what cytokines increase the expression of MHC1?
IFN-a, b, y & TNF
what cytokine induces class 2 MHC gene expression by B cells and non-professional APC?
Il-4
expression of MHC is linked with the inflammasome core components (___ and ___) which activate ____ of MHC
CITA and CIITA; transcription
the scheme for transcription and expression of class 1 MHC genes shows the correspondence between gene exons and ____. Each exon is translated to become a ____
protein domains; protein domain
mRNA transcripts are spliced to remove ____ sequences
intron
in MHC gene processing, the ___ sequence is removed after translated and before cell surface expression
Leader peptide (L)
t/f the scheme for transcription and expression of MHC2 genes is the same as that for MHC1 genes
t
t/f MHC3 is evolutionarily conserved across species
t
what are 3 genes encoded in MHC3?
- complement proteins
- TNF (for Th1 immunity)
- Lymphotoxin (for Th1 activation and recruitment of lymphocytes
MHC3 and non-classical MHC molecules are ____ to antigen presentation
accessories
non-classical MHC1 has ___(increased/reduced) expression compared to classical MHC1
reduced
non-classical MHC1 is restricted to what locations?
very particular tissues and low levels on cells
what are 2 subtypes of non-classical MHC1?
- HLA-G/Qa-2
2. HLA-E/Qa-1
where are HLA-G/Qa-2 found and what is their function?
fetal cells at the maternal interfacel involved in tolerance of T and NK cells to protect fetus from rejection
what is the function of HLA-E/Qa-1?
recognition of leader sequences from MHC peptides presented to NK cells
what are 2 subclasses of non-classical MHC2?
- HLA-DM/H2-DM
2. HLA-DO/H2-O
what is the function of HLA-DM/H2-DM?
no antigen presentation, but involved in assisting peptide loading
what is the function of HLA-DO/H2-O?
intracellular regulator of antigen presentation
where are HLA-DO/H2-O expressed?
regulated expression in B cells, thyrmic medullary epithelial cells and DC
what is CD1 and its function?
a conserved MHC1 molecule that presents glycolipid antigens to the NKT cells (different from peptides)
although CD1 is structurally similar to MHC__, they are loaded in a similar way to MHC__
1, 2
CD1 are loaded with ___
fragments from endosomal compartments (i.e. extracellular antigens)
what are NKT cells?
natural killer T cells are cytotoxic effectors with characteristics of T and NK cells (but are a unique subtype)
the functions of CD1 and NKT cells are important for recognizing ____
mycoplasma
NKT cells and CD1 have immune regulatory roles and their deletion is associated with ____
autoimmunity
how does the CD1 accomodate glycolipids?
by having a larger, deeper binding pocket compared to MHC1
what are mucosal-associated invariant T cells (MAIT)?
they are like NKT cells in that that respond to an invariant MHC class 1-related structure, MR1
MAIT recognize ____ by their ___ receptor
MR1; invariant T cell receptor
MRI presents ____ derivative in the gut to promote tolerance/responsiveness to commensals/pathogens in the gut
vitamin B2
