Lecture 20: Early Lymphocyte Maturation - T cells Flashcards
Where do T lymphocytes develop?
in the thymus
What does activation of TCR require?
interaction with major histocompatibility complexes (MHC)
What do T lymphocytes express?
CD4 or CD8 co-receptors
What are the effector functions of T cells?
involves direct killing (cytotoxic) or secretion of cytokines (helper)
What are the similarities of T cell and B cell development?
stepwise rearrangement of receptors
have to undergo strict controls of testing
eventual assembly of the heterodimeric receptor
What are the differences of T cell and B cell development?
two distinct sets of TCRs
more diverse subsets
MHC restriction
produced only in the first decade or so
Where is the thymus and what is it made up of?
just above the heart
made up of thymic stroma cells crucial for function
What do conditions affecting the thymus have major implications on?
development of immune responses
What are examples of thymic stroma cells?
intrathymic dendritic cells, macrophages and thymic epithelial cells
What is the thymus segregated into?
the cortex and medulla
What are characteristics of the cortex?
more densely pack; peripheral
mostly immature thymocytes
What are characteristics of the medulla?
less packed; central
site for negative selection - DC generally absent from cortex
What does successful maturation of thymocytes lead to (if they do not undergo apoptosis like the majority)?
successful maturation leads to formation of αβ T cells, γδ T cells and invariant T cells (e.g. NKT)
What are the stages of thymocyte maturation?
there are double negative (DN) and double positive (DP) stages
DNs can be classified into four distinct stages
What can DN cells give rise to?
all three subsets
What do CLPs that enter the thymus interact with?
TECs through Notch1
What are characteristics of DN1 thymocytes?
classified as DN1 shortly after entering through HEV and Notch signalling
germline configuration of TCR genes
CD44+ CD25-
What are characteristics of DN2 thymocytes?
undergo routing to the cortex and become responsive to IL-2
CD44+ CD25+
starts rearranging beta chain of TCR
What are characteristics of DN3 thymocytes?
joining of DJ-beta to V-beta -> if unsuccessful remains in this stage and dies shortly after
pairing of beta chain with a surrogate alpha chain to form the pre-TCR
CD44 low CD25+
What are characteristics of the pre-TCR?
analogous with pre-BCR, forms complex with CD3 chains, signalling stops beta chain rearrangement and promotes allelic exclusion, induces cell proliferation
What are characteristics of DN4 thymocytes?
rapid cell proliferation occurs
induction of CD4 and CD8
represses RAG-1 and RAG-2
CD44- CD25-
What are characteristics of DP thymocytes?
able to start rearranging alpha chain
capable of successive V alpha and J alpha rearrangements
express both CD4 and CD8
requires + selection to shut off rearrangement and progression of maturation
What is the role of positive selection?
tests the ability of DP cells to recognise MHC molecules
DP cells that do not receive signals from + selection die from neglect
What does positive selection coordinate?
the expression of CD4 or CD8
binding of MHC I promotes CD8 T cells and binding of MHC II promotes CD4 T cells
What does strength of TCR binding to MHC dictate?
subsequent activation in the periphery
Where does negative selection occur?
can occur in both cortex and medulla but predominantly in the latter
What is negative selection important for?
the removal of self reactive cells
Recognition of specific MHC:peptide complex in the ____ leads to ____ while in the ____ leads to ____.
thymus, deletion
periphery, activation
What is the role of thymic cortical epithelial cells?
express MHC important in positive selection
What is the role of medullary epithelial cells and DCs?
express autoimmune regulator (AIRE) which facilitates negative selection
What do interactions of thymocytes with thymic stromal cells facilitate?
selection
What happens to T cells which are just on the threshold of having binding that is too strong in the thymus?
conversion / commitment of cells to regulatory T cells
a small population can form iNKT cells that bind CD1 molecules
some escape to the periphery and can be rendered anergic or tolerogenic
What do thymocytes require to survive?
rescue by positive signals
