ch 5: T lymphocyte development Flashcards
the primary lymphoid organ responsible for T cell development
thymus
functions of the thymus
- promote recombination events in developing T cells
- test thymocytes TCRs to recognize MHC-peptide complexes
- test thymocytes TCRs tolerance to self-peptides
immature T cells (thymocytes) reside in the ______ while mature T cells undergo negative selection in the ______ and finish development
cortex, medulla
describe the cells found in the thymus
thymic epithelial cells: activate genes required for thymocyte development
macrophages: remove thymocytes that have not developed properly and have undergone apoptosis
dendritic cells: present self-antigens to developing thymocytes to test the functionality of the T-cell receptor
what are Hassall’s corpuscles
they are used to recruit T cell exceptions and contain epithelial cells that express an important protein called thymic stromal lymphopoietin (TSLP) that triggers Tregg development
C-kit
aka CD117, it is a receptor for stem cell growth factor
____ is secreted as a signaling molecule by thymic epithelial cells
IL-7
hematopoietic stem cells are often characterized by ________ that are present on the stem cell precursors, along with the absence of ________
cell-surface markers, lineage-specific markers
what is the role of Notch in T cell development
Notch aids in T cell proliferation and differentiation by allowing them to commit to the T lineage
explain how Notch1 signaling helps commit thymocytes to T cell development
Notch ligand from an adjacent thymic epithelial cell binds to Notch1 and proteolytic cleavage allows Notch1 to move into intracellular domain and into the nucleus of the lymphoid progenitor to affect transcription
thymic epithelial cells provide the Notch ligand and what other signal to promote proper thymocyte development?
IL-7
what is the domain that translocates into the nucleus of lymphoid progenitor cells, where it activates gene expression required for T-cell differentiation?
the intracellular domain of Notch1
during initial development in the thymic cortex, the thymocyte is called a ___________ because it does not express either coreceptor (CD4 or CD8)
double-negative thymocyte
both coreceptors (CD4 and CD8) are present on the surface of the developing T-cell, and the thymocyte becomes a _____________
double-positive thymocyte
others begin the process of positive and negative selection to test the T-cell receptor and select for a single coreceptor to ultimately become a ________________
single-positive thymocyte
___ turns on RAG1 and RAG2 and helps regulate TdT
IL-7
IL-7 is a source from ___________
thymic tissue
describe the thymocyte developmental stages DN1, DN2, DN3, and DN4
- DN1: double-neg 1, thymocytes have entered thymus and initiated somatic recomb. at T cell receptor loci
- DN2: double-neg 2, committed to T cell dev. and express CD25
- DN3: double-neg 3, somatic recomb. of beta chain and turned off CD44 expression
- DN4: active alpha chain rearrangement, express low level of CD117 (c-kit) and no longer express CD25 + CD44
possible fates of double-positive thymocytes
regulatory T cells, NK T cells, or further selection to become single-positive
what is the difference between human and mouse thymocyte development?
human lymphoid progenitor cells that have migrated from the bone marrow to the thymus shut down expression of CD34 and begin expressing CD2, CD5, and CD7. as human thymocytes continue development, they begin to express CD1. like mouse thymocytes, they do not express CD4 or CD8 and are double-negative thymocytes early in development.
what are the key 3 checkpoints a thymocyte passes to become a functional naive T cell?
- gamma-delta checkpoint: T cell that has properly recombined both the γ and δ loci is destined to become a γδ T cell
- beta checkpoint: if the β subunit recombines properly, somatic recombination is inactivated to allow the thymocyte to ready itself for the next developmental stage
NOTE: gamma-delta and beta occur at the same time during somatic recomb. - alpha checkpoint: once a developing thymocyte has properly recombined a β locus and progressed to the next developmental stage, recombination events continue at the α, γ, and δ T-cell receptor genes. if the γ and δ genes recombine properly, the thymocyte will be committed to becoming a γδ T cell. proper recombination of the α subunit locus allows the thymocyte to continue development toward becoming an αβ T cell.
the factor that determines whether a developing thymocyte becomes an alpha-beta cell of a gamma-delta cell is _________________
how fast the receptor genes recombine
if proper recombination of the _____ occurs, the _____ is lost in a signal joint of somatic recombination, and the cell cannot express a proper γδ T-cell receptor.
alpha chain, delta chain
the first T cells produced and work to protect the fetus are
gamma-delta T cells
role of gamma-delta T cells in adults?
protect mucosal membranes by recognizing unconventional antigens (ex: lipids)
____ T cells represent 3.5% of T cells in humans and require two successful recombination events therefore are not present in large quantities in humans
gamma-delta
most T cells will express the ____________
beta chain
what is the pre-T alpha chain?
since recombination of the α-chain locus does not occur until the β-chain checkpoint has been passed, a surrogate α chain must be used to assemble with the rearranged beta chain and the CD3 complex to form the pre-TCR
somatic recombination is activated through expression of ___ and ____ proteins
RAG1 and RAG2
_________ process is vital for ensuring a thymocyte does not produce more than one functional beta chain
allelic exclusion
chromatin remodeling
β-chain locus is repackaged into tightly condensed chromatin to prevent further recombination at the remaining β-chain locus when the recombination machinery is reactivated
what happens to the large number of thymocytes that do not pass the alpha and beta chain checkpoints?
they are programmed for apoptosis and are removed by resident macrophages
the alpha chain is tested at the ___ __________
ER membrane
if a functional alpha chain is produced, the developing thymocyte continues development into a _________
naive T cell
proper alpha chain rearrangement removes the possibility of producing a
gamma-delta T cell
what are the 3 possible outcomes for a double-positive thymocyte that interacts with thymic epithelial cells
- death by neglect: no binding affinity of MHC complex to cortical thymic epithelial cells, cell dies by apoptosis
- positive selection: DP cells interact with low/moderate affinity to MHC complex and survive and proliferate
- negative selection: DP cells interact too tightly with MHC complex and die by apoptosis
what is lineage commitment?
the commitment of a thymocyte to express a single coreceptor
describe the instructive model of lineage commitment
- if a TCR engages with MHC1, the interaction promotes CD8 expression and leads to CD8 thymocyte
- if a TCR engages with MHC2, the interaction promotes CD4 expression and leads to CD4 thymocyte
describe the kinetic signaling model of lineage commitment
- positively selected thymocytes will become CD4 is the T cell receptor/coreceptor signal is continuous
- positively selected thymocytes will become CD8 if CD4 signal is interrupted
- the process is skewed towards making a CD4 cell (default pathway)
single positive thymocytes move toward _____ with the help of _____ chemokine
medulla, CCR7
transcriptional activator AIRE
enables thymic epithelial cells to undergo promiscuous gene expression. has a CARD, SAND and PHD (two) domain to allow AIRE to interact with histones within chromatin of thymic epithelial cells
AIRE also acts as “gas pedal” for
RNA polymerase, it causes transcription of tissue-restricted genes and presentation of tissue-specific antigens on MHC 1 within medullar TECs
