CBG Lecture 27: T and B cell development Flashcards
Which one or more of the following statements are true of the majority of RNA viruses?
replicate in the cytoplasm
have ss genomes
give some properties of antiviral interferons
activate NK cells
can be induced in response to dsRNA production
what can infection of cells by retroviruses cause
syncytia
name a cell that can be induced in response to dsRNA production
interferon
give some properties of NK cells
They play a role in antibody-dependent cell-mediated cytotoxicity
They can directly kill virus infected cells
They are part of the innate immune response
what are some properties of human filoviruses
Are enveloped
Contain a polymerase in their viral particles
name a human virus that is enveloped and contains a polymerase in its viral particles
human filovirus
where was HIV1 probably first transmitted to humans
in Africa
name a virus with a dimeric genome
HIV
name broad process of activation of AB producing cells
clonal selection
outline process of clonal selection
B lymphocytes recognise intact pathogenic microorgs and toxins
B lymphocytes possess antigen specific receptors
binding of specific antigen results in proliferation of clonal popn of cells
antigen determines clonal proliferation
what determines clonal proliferation
antigen binding on B lymphocytes
what is involved in the cell mediated response
T lymphocytes
what is involved in the humoral response
B lymphocytes
where does generation of diversity from hematopoietic stem cell occur
in primary lymphoid organs
where does deletion of B cells occur
in primary lymphoid organs
name the primary lymphoid organs
bone marrow
thymus
name the secondary lymphoid organs
lymph nodes
spleen
what are the postulates of the clonal selection hypothesis
each lymphocytes has a single specific unique receptor
lymphocyte activated if the interaction between a foreign molecule and lymphocyte receptor bind with high affinity
after activation, the differentiated effector cells derived form an activated lymphocyte bear exact specificity of parent cxell
lymphocytes bearing “self” receptors will be deleted early in lymphoid cell
how are antibody producing cells activated
by clonal selection
what is proliferation of activated cells followed by
differentiation into plasma cells, then memory cells
what is life span of plasma cellls
4-5 days, 1-2 mnths
produce 2000ABs/second
how many ABs do plasma cells produce
2000 oer second
what is lifespan of memory cells
years to decades
how do memory cells differentiate back into plasma cells
following stimulation by same antigen
if memory cell is stimulated by same antigen, what happens to it
it will differentiate into plasma cell
which cells release cytokines
T cells
what do cytokines do
activate B cells
what is primary response
following exposure to antigen, theres slow rise in IgM followed by slow rise in IgG
following exposure to antigen, discuss IgM and IgG levels
following exposure to antigen theres a slow rise in IgM then slow rise in IgG
what is secondary response
following exposure to previously encountered antigen, theres a rapid rise in IgG and slow or no rise in IgM
discuss IgG and IgM levels in secondary response
rapid rise in IgG, slow or no response in IgM
discuss IgG and IgM levels in primary and secondary response
in primary: slow rise IgM followed by slow rise IgG
in secondary:
rapid rise IgG, slow or no response in IgM
name some granulocytes (polymorphoneuclear leukoctes)
mast cell precurosor neutrophil eosinophil basophil monocyte
outline negative selection in the bone marrow
happens when an immature B cell IgM binds to self - so is removed from the repertoire
what cells do activated B cells give rise to
plasma and memory cells
where does antibody secretion occur
in bone marrow and lymphoid tissue
outline structure of the BCR
membrane bound antibody
2 heavy 2 light chains
variable regions for antigen binding
what are the light chains of ABs called
kappa or lamda
what are the heavy chains of ABs called
theta gamma alpha delta or epsilon
which AB has greatest hinge region
IgA - bigger bidnding
which frament contains all antigen binding specificity
Fab
what is the Fab region
where antigen binding specificity is
what is the hinge region
open region - site of segmental flexibility
which section of AB is good for medical/therapeutic purposes
Fab region
without Fc region theres less chance of AB being a physical limitation - can just use Fab region to get to tumour
how many different BCRs can be produced
milli
how is diversity of BCRs generated
by rearrangement of the BCR genes; somatic recombination
what is a use for somatic combination
rearrangement of BCR genes to generate diversity of different receptors
what is somatic recombination
bits DNA with highly specific regions moved around by enxymes: unique combination of segments become joined and chains pair to give unique receptor
segments of genomic DNA within the immunoglobulin genes are rearranged in
cells of the B-lymphocyte lineage, but not in other cells.
WHAT IS the term for segments of genomic DNA within the immunoglobin genes getting rearranged in cells of B lymphocyte lineage but not in other cells
somatic recombination
how many segments is the V domain of an Ig coded by?
what are they
2 - V gene segment and J gene segment
what are light chains made up of
V and J
what segments are heavy chains made of
V D J
which sequence of AB/BCR is removed to make disulfide bonds
the L leader sequence
what happens to L leader sequence after translation
it is removed to make disulfide bonds
how many aas does V encode
variable gene segmentt encodes 95-101 aa
how many aas does J encode
joining segments
up to 13 aa
what does D stand for
diversity segment
what is junctional diversity
process of recombination at the coding joint to generate diversity - where nucleotides are added or subtracted randomly
which AB segment is not present in light chains
D - diversity segment not present in light chains
what is the structure of the pre-B cell receptor
heavy chain rearranged first expressed on the surfface as a preBcR shuts down heavy chain rearrangement then light chain rearranged BCR checked for autoreactivity if no reactivity it can exit
what is affinity maturation
when Tfh cell-activated B cells produce antibodies with increased affinity for antigen during IS. With repeated exposures to the same antigen, a host will produce antibodies of successively greater affinities. A secondary response can elicit antibodies with greater affinity than in a primary response. Affinity maturation primarily occurs on BCRs result of somatic hypermutation (SHM) and selection by Tfh cells
what do all isotype switching response start as
IgM - cells can switch to making IgA,IgG, IgD etc
what do T cells contain that BCRs dont
cytoplasmic tail
what regions present in T cellls
V(ariable) C(onstant) H(inge) transmembrane region cytoplasmic tail
how many dimers in a T cell
heterodimeric alpha beta T cell receptor
what two main groups can T cells be divided into
CD4+ - helper - class 2 MHC CD8+ = cytotoxic - MHC Class 1
what do CD4 and CD8 bind to
conserved regions of MHC molecules
what do MHC molecules do
present antigen to T cell
what class MHC does Cd4 recognise
class 2
what must T cells recognise
self MHC molecules and express CD4 (MHC2) or CD8 (MHC1)
discuss formation of variation among T cells
germline - beta chain rearranged and expressed, alpha chain rearranged and expressed
how is diversity increased for TCRs
by junctional diversity - like B cells
what processes confer diversity in BCRs
junctional diversity -add/delete nucleotides
combinatorial diversity - of V D J segments
somatic recombination because V regions are encoded by separate gene segments, which are brought
togetherto make a complete V-region gene
somatic hypermutation - after an immunoglobulin has been expressed, the coding sequences for
its V regions are modified by somatic hypermutation upon stimulation of the B cell by antigen
does somatic hypermutation occur in T cells
NO - variability of the CDR1 and CDR2 of T cells regions is limited to
that of the germline V gene segments. All the diversity in T-cell receptors is generated during rearrangement and is
consequently focused on the CDR3 regions.
what is the structural diversity of T-cell receptors is mainly attributable to
combinatorial and junctional diversity generated
during the process of gene rearrangement
which part of TCR contains highest diversity
central part, which contacts the bound peptide fragment of the ligand
which Ig isotypes lack hinge regions
Both IgM and
IgE lack a hinge region but each contains an extra heavy-chain domain
why are IgM and IgE not like the other Ig isotypes
they lack a hinge region
and contain an extra heavy domain
what are the 3 ways ABs participate in host defense
- activate complement
- opsonization
- neutralisation
how do ABs deal with bacterial toxins
neutralisation
how do ABs deal with bacteria in extra cellular space
opsonization for ingestion
how d Igs deals with bacteria in plasma
complement activation
why does dneutralisation of bacterial toxins occur
because unbound toxin can react with cell receptors, but toxin:antibody cant
why does opsonixation occur
if antibodies coat it - it makes bacteria recognizable by phagocytosis
which Igs can form multimers
IgM and IgA
which MHC Class molecules are peptides from the cytosoml bound to
MHC1 - CD8
think cytosol - cytotoxic
which MHC class molecules are peptides from vesicles bound to
MHC2 -Cd4
what are successive stages in the development of thymocytes marked by
changes in cell surface molecules
what surface changes to thymocytes undergo in T cell development
expression of cell surface proteins like CD3 complex and the coreceptor proteins Cd4 and CD8 - these surface changes reflect the state of functional maturation of the cell
what can be used as markers for stages of T cell development
particular combinations of cell-surface proteins
which two distinct lineages of T cells are produced early in T cell development - which pop was major, which is minor
alpha:beta (major pop) and gamma:delta (minor pop)
what triggers an initial phase of differentiation along the Tcell lineage pathway followed by cell proliferation
interactions with the thymic stroma
what are double negative thymocytes
thymocytes/immature T cells which dont have CD4 or CD8 receptors
discuss flowchart of T cell development
double negative thymocyte -> beta chain rearranged -> alpha and beta chanin rearranged - double positive with CD4 and CD8
what different TCRs could be generated after development
- unable to recognise MHC - useless
- able to recognise MHC - useful
- high affinity for MHC and self antigen = dangerous
what % of T cells produced in thymus die
95%
how do CD8+ cells kill
by releasing granzymes and perforin or by engagement of Fas on target cells by Fas ligand
what is T cell positive selection
double positive cells checked for their ability to recognise MHC
if no recognition - death by neglect
what happens to T cells that arent double positive
death by neglect - cant release signals
what is T cell negative selection
double positive/single positive cells with high affinity for MHC and self antigen are removed
what is role of Th1 cd4 cellsq
recognise complex of bacterial peptide with MHC Class2 and activate macrophage
direct and regulate other arms of the immune system
which T cell activates macrophages
helper T cells
Cd4
what are CTLs
cytotoxic T lymphocytes
what is role of T cells
recognise viral antigens on MHC1 - directly kill target cells with viruses
what factors regulate T and B cell development
both require interaction with stromal cell in bone marrow or thymus
both require IL-7 to sustain development
both express RAG - recombinase activation gene to joins segments
developing T and B cells are the only cells to express RAG
what is RAG
which cells express it
developing T and b cells are the only cells to express RAG - recombinase activating gene
what IL do T and B cells require for development
interleukin 7
what cells do T and B cells require interaction with
thymus/bone marrow stromal cells
