1.05 - Lymphocyte Development II Flashcards
Describe MHC Class I
Expressed on all nucleated cells
Present antigen peptides to CD8+ T cells
Describe MHC Class II
Expressed on antigen presenting cells (B cells, DC, Macrophages)
Present antigen peptides to CD4+ T cells
What are the two locations for T cell development
Derived from progenitors that arise from pluripotent haemopoietic stem cells in the bone marrow
Migrate to the thymus –> followed by differentiation
Describe the thymus
Organ in the upper anterior thorax
Two distinct regions regions: Thymic Cortex & Thymic Medulla
Colonised by Thymocytes (committed to T-cell lineage)
Thymocytes influence development of thymic epithelial cells (required for thymocyte survival)
Describe the four stages of Double Negative Thymocyte development
DN1:
- Most immature cortical thymocytes
- Germline congifuration
- No expression of TCR or co-receptors
DN2: Pro T Cell
- Expression of recombination activation genes (RAG-1, RAG-2)
- Rearrangement of T cell receptor beta chain
- Dbeta to Jbeta first
DN3: Pre T Cell
- Continued gene rearrangement (Vbeta to DJbeta)
- Cells that fail to make a successful beta gene rearrangement sat at DN3 stage and die by apoptosis
DN4:
- Proliferation
DN = Double Negative Thymocyte
Describe the Pre-T cell receptor
Inhibition of beta chain recombination
Proliferation of pre-T cells
Stimulation of alpha chain recombination
Expression of CD4 and CD8
Describe alpha chain gene rearrangement
Expression of RAG-1 and RAG-2 proteins
No D segments
Joining of V and J segments
Formation of the complex alpha/beta TCR leads to co-expression with CD3 and z proteins on the cell surface
RAG expression down regulated, alpha chain gene rearrangement ceases
Thymocyte now responsive to antigens
Alpha chain rearrangement continues until either a productive rearrangement with a positive selection or the cell dies by apoptosis
Describe antigen recognition by T cells
TCR recognises short amino acid sequences
Protein must be unfolded and processed into fragments
Peptides only recognised when bound to an MHC molecule
Describe Positive selection of T cells
Double positive cells interact with MHC Class I and II molecules expressed on thymic epithelial cells
Thymocytes with a TCR that binds self peptide-Self MHC with low avidity survive
Thymocytes with a TCR that does not recognise self-MHC die by apoptosis
Describe Negative Selection of T cells
Thymocytes that bind strongly to self-peptide-self-MHC complex die by apoptosis
This removes cells that are potentially auto reactive against self antigens
T Cells with low affinity for the complex do not receive survival signal and undergo apoptosis
T cells that don’t recognise MHC undergo apoptosis
Remaining T cells go on to mature in the thymus and migrate to periphery.
What happens to double positive cells that survive positive and negative selection?
Down regulate expression of either CD8 or CD4. Leave thymus via the blood stream and are now tolerant to many self-antigens
What are the differences between B & T Cells receptors?
TCR rigid conformation - binds to surface of host cells
Ig molecule - flexible to enable binding to antigens at surface of B cell or in solution
Ig able to bind many different types of antigen (CHO, Proteins, DNA, lipids), TCR generally only peptides
TCR doesn’t exist in a secreted form
What are the differences between B and T cell development?
TCR doesn’t change in response to exposure to antigen (contrast with somatic hypermutation and isotype switching in B-cell development
What are some similarities between B & T cell development?
Stepwise rearrangement of antigen-receptor genes
Sequential testing for successful gene rearrangement
Formation of a complete heterodimeric antigen receptor
