lecture 4 Flashcards
where do T cells develop?
thymus
what does the Pax5 gene do?
allow the development of a B lymphocyte to a B cell
what do B cells develop from?
haematopoietic stem cells in the bone marrow that express PAX5 transcription factor
what does the development of B cells include?
- rearrangement of genes
- expression of Ig genes and lymphocyte
- removal of self reactive cells
what molecule allows early recognition of a B cell?
CD19
what happens if an immature B cell bound to self cell surface antigen is removed?
negative selection in the bone marrow
what happens if a mature B cell that’s bound to foreign antigen is activated?
- B cell leaves bone marrow
- goes into blood and lymphatics
- if recognises outside bone marrow it releases the B cell receptor as an antibody
how do activated B cells give rise to plasma and memory cells?
- some cells keep antibody on surface as a receptor which form memory cells as have long life span
what is a pre-B cell receptor?
heavy chain with a surrogate light chain
how are pre-B cell receptors formed?
- heavy chain genes rearrange first
- moves to cell surface with Ig alpha and beta
-expressed with surrogate light chain
what does the pre-B cell receptor test?
- if the heavy chain can bind to the surrogate light chains
- if yes, signal dissent once the binding occurs and an actual light chain is produced
what occurs after a pre-B cell receptor is formed?
- light chains rearrange and displace chains associating with the H chain to form IgM BCR
what are immature B cells?
B cells which have put together a heavy and light chain
how is the pre-B cell receptor formed?
- B cell initially doesn’t have BCR as rearranging the heavy chain
- preB, at surface, attempts to bind all heavy chain rearrangements- if successful = heavy chain works
- if works, signal sent to B cell to arrange light chain to match
what proteins help with signalling machinery?
Ig alpha and Ig beta
what is the function of the pre-BCR?
- delivers signal to pre-B cell that H chain is functional
what occurs once this signal is sent?
- turns off RAG1&2
- cell division occurs to replicate enough heavy chain
- surrogate light chain expression stops
- RAG1&2 turned on again to recombine the light chain sequences
- light chain rearrangement starts
what are RAG genes needed for?
gene rearrangement
what does each individual B cell express on their light chain?
EITHER kappa or lambda
what has a 1 in 3 success rate?
rearrangement of genes to produce successful chains
what happens if both the H and L genes fail to rearrange well?
cell dies
what occurs following successful H chain rearrangement?
- preB cells that initially fail to generate non productive rearrangements of light chain kappa genes can be ‘rescued’ by up to 10 further rearrangements at same locus
what happens if rearrangement at kappa loci doesn’t work?
the lambda locus begins to rearrange
what expresses membrane IgM only?
immature B cells
what do immature B cells that bind multivalent self antigens undergo?
- clonal deletion- cell dies by apoptosis if self reactive BCR
- receptor editing- B cell can avoid death if turns back on its RAG genes and try to make another light chain
what occurs when a soluble self antigen is bound?
cell becomes unresponsive (anergic) - BCR on surface decreases, sneaks out bone marrow as not enough to be killed
what happens to cells that don’t express PAX5?
- leave bone marrow quickly with no rearranged receptor
-enter thymus as thymocytes (on way to becoming T cells)
where do T cells originate from?
bone marrow stem cells
how are T cell developed?
- receptor genes are rearranged once in thymus
- pre-T receptor is expressed
- self reactive T cells are eliminated by negative selection
what happens if the T cell recognises self MHC molecules which thymus cells are expressing?
the T cells are positively selected as can bind the MHC so useful later on
what do T cells expressing alpha/beta TCR bind with?
self MHC that’s expressed in the thymus
what signal do thymocytes require to turn into a T cell?
signal from a notch molecule
where do activated T cells migrate to?
site of infection
where do mature T cells migrate to?
peripheral lymphoid organs
what occurs when developed T cell progenitors migrate to thymus?
- cells continue their development by rearranging their antigen-receptor genes
-undergo repertoire selection
what happens once the precursors develop into thymocytes?
- rearrange TCR genes (beta first) and express TCR
- acquire other markers eg. CD3, CD4, CD8
- undergo positive and negative selection while still in thymus
what is the thymus?
- bi-lobed organic the anterior mediastinum
- each lobule has outer cortex and inner medulla
what cells are present in the thymus?
lymphoid, epithelial, macrophages, dendritic cells
how do pre-thymocytes enter the cortex?
via blood vessels from bone marrow
what occurs once the thymocytes are in the thymus?
- rearrange TCR beta genes
- expressed along with pre-T cell receptor
- cells proliferate
- TCR alpha genes rearranged
what does the surface of T cells express in and out thymus?
- have CD3, 4 & 8 when in thymus
- once out thymus, have CD4 or CD8
what is the function of CD3 complex?
-transmits signal to T cell nucleus following TCR recognition of antigen
what’s the difference with delta/gamma TCR?
-they don’t express CD4 or CD8 markers
-less diverse
-expressed on separate T cell population but most die
-recognise different antigens
-unsure whether undergo positive and negative selection
how do T cells become gamma delta T cells?
by coming out the thymus - not quite understood by scientists
how are both positive and negative cells produced from only negative?
-double positive CD4 and 8 undergo positive and negative selection in the thymus to make sure capable of recognising MHC
-results are either cd4+- or cd8+- on surface
what might T cells expressing a randomly rearranged alpha/beta recognise?
- self MHC plus peptide from ‘foreign’ antigen (immunity) - KEEP
- recognise self MHC plus peptide from ‘self’ antigen (autoimmunity) - ELIMINATE
- not be able to recognise self MHC - ELIMINATE
how are T cells positively selected?
-occurs when double positive T cells recognise MHC on cortical epithelial cells in thymus
-if doesn’t recognise then apoptosis occurs
-rearrangement gives random TCR repertoire
where do positively selected cells move?
to the medulla
where does positive selection occur?
in the cortex by cortical epithelial cells in thymus
how are T cells negatively selected?
-T cells which recognise self MHC on thymus dendritic checks/ macrophages with high affinity are negatively selected
what cells allow negative selection?
dendritic cells and macrophages in thymus
what happens to cells with no affinity?
they die as only cells with affinity are positively selected
what is the ultimate goal from positive and negative selection?
-a population of T cells with low affinity for self peptide and self MHC
-more likely to have high affinity for self MHC when presenting peptides derived from pathogens
what happens to the T cells that survive thymic selection?
-express TCR capable of binding self MHC
-depleted of self reactive cells
-exit thymus as mature, single positive T cells
what do CD8+ T cells recognise?
antigens in association with MHC class I
what do CD4+ cells recognise?
antigens in association with MHC class II
