T-cell maturation/development/differentiation Flashcards
Selecting TCRs are reactive to
foreign peptide-self MHC but not to self-peptide/self MHC- central tolerance becasue it occurs in thymus and not in periphery.
Thymic epithelial cells serve as
antigen presenting cells expressing MHC class I/ self peptide or MHC class II/ self peptide for thymocyte TCR’s to scrutinize
TCR’s structure
Two polypeptide chains Alpha/Beta or Gamma/Delta each with variable and constant domains
TCR alpha variable domain
VJ segments
TCR beta variable domain
VDJ segments
somatic recombination is the process y which
gene segments are selected and combined to form unique variable region in the TCR alph and TCR beta changes
Somatic recombination is initiated by
recombinases which are products of RAG(recombination activating gene)-1 and RAG-2 genes
V’s D’s and J’s are randomly selected and combined to form
variable region of TCR alpha and TCR Beta
Rearranged genes are transcrbied to
mRNA genes whech are translated into an alpha and beta polypeptide chain to become a T cell receptor.
allelic exclusion
successful recombination of somatic recombination inhibits other allele recombination
unsuccessful rearrangement of DNA on one allele leads to
attempted recombination on another allele.
diversity of T cell is the result of
–multiple copies of germline V,D, and J segments, – Random selection and combination of V, d, and J segments, – Juncation diverstity generated by addition and deletion of bases. –random assortment of TCR alph and beta chains
junctional diversity is created when
DNA nucleotide are deleted or inserted at V,D, or J, gene segment junctions in order to maintain an open reading frame.
each TCR s expressed in assoction with
five invariant polypeptides called CD3
CD3 serves to link
the antigen binding receptor of the T-cell signaling pathway.
variable regions are constructed from
segments termed Variable(V), Diversity(D), or Joining(J)
during activation of recombination the locus that encodes V, D, and J is
cut and recombined to make an intact gene encoding varible regions in TCR alpha and beta polypeptide chains.
during recombination process intervening unselected V, D, J are
deleted.
when the recombination has not resulte dn open reading frame, nucleotids are
incorporated by a template indipendent of DNA poymerase, terminal deoxynucleotidyl transverase (Tdt) which allows the transcription and transition to form the polypeptide
thymic cortex processes
-entry of bone marrow derivee of lymphoid progenitors in the thymus corticomeduallary junction – expresion of preTCR rcomplex(rearranged beta chain, CD3, and pre T Alpha) –expression of both CD4 and CD8 and +pre TCR complex – Expression of TCR complex (rarranged alpha and beta chain) +CD3,4,8) –Selection of DP thymocytes that express TCR’s useful to the immune system –Lineage determination
thymic medulla processes
-Expression of AIRE gene in mTEC to allow expression of tissue proteins in the thymic medulla –interaction of SP thymocytes with mTEC’s to select autoreactive cells. –negative selection– export of three lineages of Tcells CD4+nTREG, CD4+Thp and CD8+ pCTL
AIRE protein is a
transcription regulator
lymphoid progenitors enter the thymus at
the corticomedullary junction
lymphoid progenitors migrate through the parenchyma to
the outer regions of the thymic cortex
lymphoid progenitors interact with
the thymic epithelial cells, which intiations differentation of the progenitors.
CD2 is one of the first
molecules to be expressed on the T cell surface and remains for the life of the cell
Thymic tolerance begins with
allelic exclusion of the TCR beta chain and expression of CD3 and pre T alpha to form a pre TCR complex
double positive thymocyes are
characterized by the cell surface expression of both CD4 and CD8 and also preTCR complex this may signal somatic recombination of TCR alpha chain.
after double positive thymocytes are there the TCR alpha polypeptide
is transcritbed follwoing somatic recombination and allelic exclusion. during this preTalpha chain is downregulated for the cell surface expresion of TCR-CD3 complex.
double positive thymocytes are selected to
live or die depending on interactive avidty of their TCR self antigen/self MHC on thymic epithelial cells and other molecules expressed on the two cells
interactive avidity depends on
intrinsic affinity of TCR for self antigen/MHC complex, –Density of TCR – Density of self antigen/MHC complexes on the thymic epithelium – the density of antagonist peptide complexs – interactino of a variety of accessory molecules and adhesion molecules with thier counterparts on the thymic epithelium.
Death by neclect.
insignificant interactive avidity of the thymocyte with thymic epithelial cells
negative selection
recognition exceeds a pre-determined threshold and thymocytes are clonally eliminated or functionally inactived by an active process.
negative selection occurs whenever
triggering threshold avidity for Tcells is exceeded.
the initial elimination of potential self reactie cells occurs in
the thymic cortex.
negative selection is a consequence of
high avidity interactions of the TCR for self antigen/self MHC occuring in the absence of CD4/CD8 interactions with MHC
positive selection
occurs in the medulla, the avidity of recognition is intermediate and results in preferntial expansion of T cells.
after selection there is
transition from double positive thymocytes to single positive,
function of T-cell is determined at
lineage determination when double postive becomes a single positive.
Aire exprssion leads to
extopic expression of tissue restricted proteins in mTECS
Interactive avidity in the medula includes
CD8 and CD4 interaction with MHC class I or Class II on mTEC and tissue restricted proteins/MHC comlexes are displayed on mTECs
medullary negative selection
destruction of potentially autoreactive Tcells
Lympohcytes leave maturation sites via blod and
either seed the secondary lymphoid tissue or recirculate in immuno surveillance
migration of naive lymphocytes from blood into lymph occurs at
specialized post capillary venules called high endothelial venules
lymphocyte rolling is induced by
interactino of L-selectin on lynpohcytes with ligand on endothelial cells.
integrins(LFA1) on lymphcytes increases
adhesiveness and stable binding to HEV
lymphocytes secerete
matrix metalloproteinases which degrades cologen to generate channells into the basement membrane
lymphocytes enter teh tissue through
transendothelial migration
if the lymphocyte doesn’t encounter an antige in the lymph node
it starts immunosurveillance in the lymphatics.
