Antigen Recognition Flashcards
receptor types
B cell receptors
T cell receptors
antibodies (soluble)
B cell receptors are composed of
surface Ig and two invariant chains (Iga and Igb)
these ensure surface expression of immunoglobulin and also function in signal transduction
T cell receptor complex is composed of a
aB heterodimer associated with invariant sequence proteins forming the TCR complex
the associated proteins form the CD3 complex to ensure cell surface expression of the TCR and the signal tranduction-CD3Z
overview of lymphocyte development
- committment of progenitor cells
- proliferation of progenitors
- sequential and ordered rearrangement of antigen receptor genes
- differentation of effectors
Clonal selection
gene rearrangement events occur in the absence of the antigen.
allelic exclusion is
NON specific
clonal selection overview
lymphocyte clones with diverse receptors arise in generative lymphoid organs
clones of mature lymphocytes specific for many antigens enter lymphoid tissues
antigen specific clones are activated by antigens
antigen specific immune responses occur
major mechanisms for generation of lymphocyte receptor diversity is
combinatorial diversification
junctional diversity
somatic hypermutation
combinatorial diversification
multple germ line genes
V-J or V-D-J somatic recombinations
junctional diversity
addition of nucleotides during process of D-J or V to DJ joinng
somatic hypermutation
point mutations occuring in fully assembled V-J and V-D_J regions during an immune response.
provides a significant source of Ab diversity
mechanisms for accounting for immune diversity for BCR/ab and TCR are
identical!
prodcution of heavy chain for BCR is same for
production of b chain in the T cells
production of light chain B cells is same for
production of A chain in the T cell
somatic hypermutaiton does not occur in
TCRs
comibinatorial diversity: VDJ rearrnagment
- D-J rearranges then
2. V-DJ rearranges
Recombination signal sequences function to
provide recognition sites for recognition enzymes that cut and rejoin DNA bits
Ensure gene segments are joined in the correct order, esp. in heavy chain VDJ
RAG1 and RAG2
recombination activating genes only made by lymphocytes, encode for these two necessary components of recombinase
Junctional diversity: at the junction between D and J, there is often an insertion of nucleotides which is catalyzed by the enzyme
TdT
Junctional diversity: TdT catalyzes the random
polymerization of nucleotides into DNa without the need for a template
Junctional diversity: P nulceotides added to asymmetrically cleaved
hairpins in a templated manner
this leads to further diversity in teh third hypervariable region
Junctional diversity: recombination between V-J and VDJ is not
always perfect
errors tht occur in the recombination event that brings the V region next to the J or D regions or the D region next to the J region can lead to frameshifts!
Junctional diversity: frameshift errors can
triple the diversity generated by DJ and VDJ joinning
the diversity generated by this mechanims occurs in the hypervariable region
lots of diagrams..know?
know
?
the second type of combinatorial diversity happens after both
receptor chains have been rearranged, transcribed and translated
the two different receptor chains (heavy and light in Ig, or a and B or y and D in TCR) are
combined to make the antigen binding site
signals from thr pre-BCR are responsible for
the largest proliferative expansion of B lineage cells during B cell development
signals to irreversibly inhibit rearrangement of the Ig heavy chain locus on the other chromosome, allelic exclusion
allelic exclusion
an individual B cell can express one heavy chain encoded by only one of the two inherited alleles
ensures that every B cell will express a single receptor, thus maintaining clonal specificity
alternative splicing of heavy chain mRNA: M and D constant regions
the pre-mRNA can be processed in two ways, one to bring the VDJ next to the Cu gene and the other to bring the VDK next to the Cd gene
the resulting mRNAs have teh L, V, D, J and Cu or Cd exons continuous and will encode for a mu and a delta chain, respectively
distinguishing self from nonself
selection deletes or functionally inactivates cells that display antigen receptors that are self-reactive
tolerance is acquired by immature B cells that do NOT become activated when challenged with self-antigen
rescue of self-reactive B cells by receptor editing
occurs in developmentally arrested, immature B cell
RAG protein synthesis remains on for additional rearrangement of light chain genes
if new light chain is not reactive with self antigen, then tolerance is established and the B cell will mature
receptor editing assesses the compatibility of receptors produced from successive gene rearrangements
DOES NOT OCCUR in T CELLS
thymus organization
different regions of the thymnus are distinguished by teh cells present and influence the developmental events of T cells
thymic cortex is outer cortical region
medulla is inner cortical region
peaks in puberty and declines after
the immature T cells contained within the thymus are called
thymocytes
they are embedded in a network of epithelial cells call thymic stroma
express both classes of MHC
the thymus is a primary lymphoid organ involved in the
production of mature lymphocytes, not antigen presentation
the only route by which progenitor cells enter the thymus and mature T cells leave is via the BLOOD
signals for the pre-TCR are responsible for
the largest proliferative expansion of T lineage cells during T cell development
signals to irreversible inhibit rearrangement of the B chain locus on the other chromosome, allelic exclusion
allelic exclusion
an individual T cell can express one B chain encoded by only one of the two inherited alleles
ensures that every T cell will express a single receptor, thus maintaining clonal specificity
the TCR will interact with either a
class I or class II MHC
combinatino of TCR and co-receptor is double checked
double positive thymocures undergo positive selection
establishment of self-restirction, recognition of self MHC
double positive thymocytes undergo negative selection
establishment of central tolerance, T cells do not become activated by self antigen
after positive selevtion, thymocytes are self-MHC restricted but
they may still be able to react with self-antigen
T reg: peripheral supressors
small population of self-reactive CD4 T cells become T regs
inhibit self-reactive Th1 cells in teh periphery
express CD4 and CD25 on surface
use FoxP3
not all self antigens are present in bone marrow or thymus, some can be
tolerized in the periphery if they encounter and respond to self antigen
VDJ rearrangement of the heavy chain
germline DNA underogoes somatic recombination to make DJ and then another somatic recombination to make VDJ and then Cu and Cd
happens by palindromic
hairpins that are cut by RAG1 and 2 (VDJ recombinases)
juntional diversity occurs at teh
hairpin turn between D and J
VJ rearrangement on the light chain undergoes
the same thing without the D and uses RAG and TdT
after DNA rearrangement,
transcripton and translation take place as normal
memorize two charts
charts!
Cu and Cd are added via
alternative splicing of the heavy regions on B cell receptros
B cells that react to self are either
killed via apoptosis or made into anergic B cells
T cells are initially
double positive as CD4 and CD8 and then they are “trained” to bind CD4-MHCII and CD8-MHCI
abberant B/T cells can be pruned at three levels
at the Pro-B/T cells phase if they fail to express pre-antigen receptor
after the pre-B/T cell phase if they dail to express antigen receptor
and at positive/negative selection. If they have a strong antigen recognition to self, they are negative selevted for and die! weak antigen will be positively selected for and live!
