L12, T cell development and activation Flashcards
recap: where do T cells develop?
in the thymus
where do the T cells originate from?
bone marrow
T cells that travel from the bone marrow into the thymus are known as …
thymic settling precursors
precursor cells are not committed to …
becoming a T cell yet
what are developing T cells called?
thymocytes
what do microenvironments provide within the thymus?
membrane-bound and soluble signals that regulate maturation during the development of T cells
what are the two phases of T cell development?
- early thymocyte development
- selection events
early thymocyte development is …
largely TCR-independent
what are the 3 specific events during early thymocyte development?
- commitment of hematopoietic precursors to the T cell lineage
- initiation of antigen receptor gene rearrangements (TCR)
- expansion of cells that successfully rearrange one of their TCR gene = beta selection
what are double negative stages? and how many are there?
absence of expression of CD4 and CD8 molecules
4 double negative stages
what markers can be used to identify different DN stages?
- c-Kit: also known as CD117 = receptor for stem cell factor
- CD44: adhesion molecule
- CD25: IL-2 receptor alpha chain
what do DN1 thymocytes do?
migration to thymus
DN1 markers = …
c-Kit++CD44+CD25-
what do DN2 thymocytes do?
rearrangement of TCR, sigma- and beta chain; fully committed to T-cell lineage
DN2 markers = …
c-Kit++CD44+CD25+
what do DN3 thymocytes do?
make a major decision: join the ysigma or alpha-beta T cell lineage / expression of pre-TCR; beta-selection
what do most of the ysigma T cells do?
leave the thymus as mature DN y-sigma T cells
DN3 markers = …
c-Kit+CD44-CD25-
formation of the pre-TCR involves …
- a successfully rearranged beta-chain
- pre-T alpha-chain
- CD3 molecules
what does signaling through the pre-TCR trigger?
a cascade of events that starts with the maturation of DN3 into DN4
DN4 markers =…
c-Kit(low/+) CD44-CD25-
what is the function of DN4 thymocytes?
proliferation, allelic exclusion of beta chain locus; alpha chain locus rearrangement begins; becomes DP thymocyte
development of CD4+CD8+ double-positive stage
selection events are ….
largely TCR-dependent
double positive thymocytes are characterized by …
the expression of both CD4 and CD8 markers
what percentage of cells do DP contribute to in the thymic cortex?
80%
what do DP thymocytes express at their surface?
a fully mature alpha-beta TCR/CD3 complex
what are the distinct selection processes that DP thymocytes go through?
positive and negative selection
positive selection = …
selection of thymocytes bearing receptors capable of binding self-MHC molecules (MHC restriction)
negative selection = …
selection against thymocytes bearing high-affinity receptors for self-MHC/peptide complexes (self tolerance)
what are self-antigens presented by?
cortical thymic epithelial cells (cTECs), to mediate positive selection
what triggers maturation of T cells?
low/intermediate affinity interaction between the TCR and MHC
what does maturation of T-cells trigger?
commitment to CD4+ or CD8+ single-positive (SP) T cell lineages
how many T cells are not selected?
about 90-96%
what are the 3 different models of T-cell lineage commitment?
- instructive model
- stochastic model (random)
- kinetic signalling model
what other lymphocyte types can DP thymocytes commit to?
- NKT (natural killer T cells)
- intraepithelial lymphocytes (IEL) - most of which are CD8+
- Regulatory T cells (TREG) - another CD4+ subset different from CD4+ Th cells
what transcription factor do medullary thymic epithelial cells express?
autoimmune regulator - allows cells to express tissue-specific antigens (TSA) from all organs
what do high affinity TCR-MHC/peptide interactions result in?
negative selection = clonal deletion
what are the 3 signals in T cell activation?
- TCR signaling
- costimulatory interaction
- cytokine signaling
What happens with T cells in order to mount a response that is appropriate against a given pathogen?
T cells can be polarized towards different subsets with specialized functions
what are the 3 factors influencing polarization?
- polarizing cytokines
- master gene regulators
- effector cytokines
What kind of pathogens are detected in type 1 response (Th1 polarization)?
intracellular pathogens inducing cell-mediated immunity (most viruses, some bacteria and fungi)
what happens in the type 2 response (Th2 polarization)?
pathogens inducing humoral immunity, particularly extracellular parasites
what is the polarizing cytokine in the type 1 response?
IL-12
what is the polarizing cytokine in the type 2 response?
IL-4
what are the master regulators in Type 1 response?
STAT4 –> T-Bet
what are the master regulators in Type 2 Response?
STAT6 –> GATA-3
what is the effector cytokine produced in Type 1 response?
IFN-y
what are the effector cytokines produced in Type 2 response?
IL-4, IL-5, IL-13
what are the distinct microenvironments in the thymus?
- subscapular cortex
- cortex and cTECs
- Corticomedullary junction
- Medulla and mTECs
description of DN1 development
migration to thymus
description of DN2 development
TCR gamma, sigma, and Beta-chain rearrangement; T-cell lineage commitment
what do DN3 thymocytes express?
pre-TCR
description of DN4 development
proliferation, allelic exclusion of beta-chain locus; alpha-chain locus rearrangement begins; becomes DP thymocyte
