11 - Lymphocyte Development Flashcards
Immature T-cells entering the thymus are __________ to becoming __________ and _______________.
are not yet committed to becoming a lymphocyte and express no antigen specific receptors and co-receptors
T-cells leaving the thymus are _____ T-cells and _______.
mature and functional T-cells and express unique & specific antigen-specific T-cell receptors and co-receptors
What are the 2 requirements of T-cell receptors?
self-tolerant | restricted to self-MHC
What does self-tolerant mean?
doesn’t react with self-peptide
Where does T-cell development occur in?
thymus
Where does early T-cell precursor development occur in?
bone marrow
What is the double negative stage of T-cell development?
thymocyte is not expressing both T-cell receptor and co-receptor
What are thymocytes?
T-cells that have not been differentiated and committed yet to T-cell development
What is the positive stage of T-cell development?
thymocyte expresses BOTH T-cell receptor and BOTH CD4 and CD8 co-receptors
What is the single positive stage of T-cell development?
T-cell will be single positive and be committed to specific subset either CD4 or CD8, not both
Which stage does TCR gene segment recombination happen?
double-negative stage
What are mature naive T-cells?
T-cells that are committed to either CD4 or CD8 but have not came across antigen and have not been activated
What are the 2 main stages in which T-cell development occurs in?
early thymocyte development | T-cell maturation
What are the 3 events that happen during early thymocyte development?
hematopoietic precursors commit to T-cell lineage | TCR gene recombination | expansion of thymocyte post-recombination
What are the 3 events that happen during T-cell maturation?
positive selection | negative selection | lineage committment
What is positive selection?
choose T-cells that can recognize self-MHC and binds to it with low affinity
What is negative selection?
remove T-cells recognizing self-protein or have a high affinity to self-MHC
What is lineage commitment?
T-cells commit to either CD4 or CD8 and become effector cells
What commits hematopoietic stem cells to the T-cell lineage?
the Notch receptor
What is the beta selection step in the negative stage during early thymocyte development?
tests the pre-TCR to see if it is signaling correctly == full functioning receptor»_space;> cell will undergo proliferation
What is the receptor for IL2?
CD25 and IL2R
Which step during T-cell maturation ensures that the T-cell is restricted to self-MHC?
positive selection
Which step during T-cell maturation ensures that the T-cell is self-tolerant?
negative selection
At what “form” are the T-cells entering T-cell maturation?
double-positive form expressing both CD4+ and CD8+
What are cortical thymic epithelial cells (cTEC)?
cells expressing high levels of MHC classes I and II
What are the 3 outcomes when T-cells encounter self-peptide/MHCs? What are the percentages for each outcome?
can’t bind (90-96%) | bind too strongly (2-5%) | bind just right (2-5%)
What happens to the T-cell if it cannot bind to any MHC?
no interaction stimulating these receptors to stay alive = deleted by neglect
What happens to the T-cell if it binds too strongly to MHC/self-peptide?
suggests it will be self-reactive = will be negatively selected against = cell dies via apoptosis
What happens to the T-cell if it binds just right to MHC?
kept and move onto lineage commitment step
Why will lineage commitment happen during positive selection? What is it testing?
testing whether TCRs are binding to MHC | the MHC T-cells bind to the best = suggests the co-receptor it is expressing that is stabilizing the interaction | this can shift the T-cell from DP to SP
What is central tolerance? Where does it happen?
negative selection = establishing self-tolerance in T-cells | thymus and primary lymphoid organs
How do we get all of the self-protein to be expressed and presented to TCRs to make sure it doesn’t react with other organs?
AIRE protein
What is the AIRE (autoimmune regulator) protein?
turns on transcription factors of all of our genes | expressed in the mTEC
What is mTEC?
expresses AIRE protein and ensures that all of the proteins in our bodies are expressed
How are T-cells that are binding to MHC on mTEC deleted?
clonal deletion via apoptosis
What is peripheral tolerance?
self-tolerance that can happen outside of the primary lymphoid organ
How does T-reg keep T-cells in check?
by suppressing or putting a break on immune responses
What are the 4 ways T-reg cells negatively regulate immune responses?
deplete cytokines stimulating cells (via IL2R or CD25) | produce inhibiting cytokines (IL10) | inhibit APC activity | directly kill T-cells
What are 3 peripheral mechanisms of tolerance that protect against autoreactive thymocytes?
“hidden” self-antigens are due to APCs lacking correct co-stimulatory molecule needed to initiate immune response | self-antigens presented by non-APCs = prevents initiation of autoimmunity | T-cells become anergic due to absence of co-stimulation
What are the 7 defining characteristics of T-cell selection/development?
negative selection | positive selection | lineage commitment | T-cell commitment = Notch | TCR gene recombination | thymus | different subsets
Each B-cell circulating in the boy express a ____.
novel and unique antigen receptor
What are stromal cells?
microenvironment that helps B-cells develop | in the bone marrow
What is B220+?
marker for pre-pro B-cells (they develop this signal)
What antibody is first expressed on every B-cell post-genetic recombination?
IgM
How are B-cells selected?
negative selection ONLY against self-protein = clonal deletion stage | (no positive selection because no MHC molecule interaction needed)
What is receptor editing in immature B-cell development?
if receptor is reacting a little bit with self-protein = light chain of receptor will be edited
Where does central tolerance for B-cells occur in?
bone marrow (clonal deletion and receptor editing)
What is the PALS area in lymphoid tissue?
the T-cell zone in the lymphoid tissue where B-cells interact with T-helper cells that will help finish its maturation stage
