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Immunology Test 4
Ch 7 & 8
Terms in this set (72)
Development (maturation) of T cells, where does it happen?
What gene segments are rearranged for the alpha and beta chains?
Are the RAG genes used in the rearrangement?
What makes up a pre-TCR?
-surrogate alpha chain(pre-t alpha)
-cd3 proteins( gamma:epsilon, epsilon:delta)
Know what IL-7 and Notch-1 do and when they exert their influence on developing T-cells.
IL-7 receptor: binds IL-7 on T-cells (coming from the thymic stromal cells) and tells T-cell what to do next in its maturation.
IL-7 stimulates the differentiation of multipotent (pluripotent) hematopoietic stem cells into lymphoid progenitor cells. Also stimulates proliferation of lymphocytes.
NOTCH-1: at all stages of maturation in thymus signals are sent through its receptor to drive T-cell in their differentiation.
Involved in the maturation of both CD4+ and CD8+ cells in the thymus.
DiGeorge's Syndrome. What is the cause? What chromosome is involved and what organ is involved?
DiGeorge's syndrome is caused by "A deletion in chromosome 22 in which the thymus fails to develop and T cells are absent". symptoms similar to SCID.
"Double negative" thymocytes; Why are they called this and where would you find them in the body?
Double negative- thymocytes = no expression of CD4 or CD8 , Location: thymus
Double positive-thymocytes = "Successful rearrangement of a beta-chain gene induces expression of the two co-receptors (CD4 & CD8)". You would find these in the inner cortex of the thymus.
Are RAG-1 and 2 working in somatic recombination of T-cells gene also? What about the 12/23 rule (1/2 turn rule)?
But during cell proliferation signaled by pre-TCR, expression of RAG1 & 2 are repressed (allelic exclusion)
Which takes place first positive or negative selection? Where does positive selection take place and where does negative selection take place?
Positive selection (thymic cortex) takes place first, then negative selection (cortex - cortico-medullary junction).
-Proliferation and differentiation to double positive thymocytes (double - thymocytes = don't express CD8/CD4 at sub- capsular zone),
-positive selection (double + thymocytes),
-negative selection (double + thymocytes)
-entry to circulation (mature, self-restricted, single positive = CD8 or CD4)
Lifespan or a T cell, short or long compared to a B-cell?
Life span of T-cell is long lived when compared to a B-cell. The reduced productivity in thymus over the years does not seem to affect the overall effectiveness of T cell immunity.
If you are heterozygus for the MHC (HLA) genes how many presenting MHC molecules do you have?
When you are heterozygous for the MHC (HLA) gene you have 12 different MHC 1 & 2 presenting molecules.
Thymocytes gene rearrangement; beta, gamma and delta chain genes (when)
The beta, gamma, and delta chain genes in the thymocyte rearrange at the same time during the double negative thymocyte production before the first checkpoint and after the committed double negative T-cell progenitor.
Deletion of the delta chain genes how does this happen and when does this happen?
"a rearrangement at an alpha-chain locus results in the deletion of the complete delta chain locus from the chromosome" happens after uncommitted double positive thymocyte
Which type of T cell receptor predominates alpha beta or gamma delta?
alpha and beta = majority
gamma delta lineage = minority
Rearrangement of a beta chain, how many possible attempts do they have to make a functional rearrangement
When rearranging the beta chain there are 4 possible attempts to make a functional rearrangement.
When are CD 4 and 8 co-expressed, before or after beta chain rearrangement? When is a thymoctye considered a single positive cell (before or after positive selection)?
CD 4 & 8 are co-expressed after B-chain rearrangement. A thymocyte is considered a single positive cell after positive selection
What is the positive selection? Where is it done, what cells mediate it, what is being checked and what happens to the T-cell?
Positive selection makes sure Tcell interacts with self-MHC if not undergoes apoptosis.
Positive selection also determines whether a double positive thymocyte matures into a CD8 or CD4 T cell
"Positive selection is the process by which this small population of T cells that reacts with the individual's own MHC molecules is selected." "Positive selection takes place in the cortex of the thymus and is mediated by cortical epithelial cells bearing complexes of class I and class II self-MHC and self-peptides.""interactions between the TCR of thymocytes with self-MHC and self-peptide are tested.If a peptide:MHC complex is bound by a thymocyte within 3-4 days of expressing a functional TCR, then a positive signal is delivered to the thymocyte.A thymocyte that does not receive a signal dies by apoptosis and is removed by macrophages."
Pre-TCR (look closely at the figures and signals that it provides).
Pre-TCR complex is composed of:
-Beta chain & surrogate alpha chain (pre-T alpha)
-CD3 complex (2E, 2Z, G, D)
Signals are 4:
-Stop Beta chain arrangement (stop RAG 1 & 2)
-Express CD4 and CD8
-Start alpha chain arrangement
What happens to the T-cells that fail positive selection?
A T-cell that fails positive selection does not receive a signal, dies by apoptosis, and is removed by a macrophage.
Positive selection and alpha chain rearrangement and number of possible receptors on the surface.
" Rearrangement of the alpha-chain locus continues throughout the 3-4 days of positive selection.""Once a T cell is positively selected, rearrangement of the alpha-chain stops.""Some double positive thymocytes can express two alpha-chains (one from maternal allele and one from the paternal allele)"
One T cell could have 2 selected TCRs, one is usually non-functional.
Process of negative selection; TCRs; self-MHC and self-peptides; mediated by several cell types; dendritic cells and macrophages; occurs in the thymus.
"Negative selection serves to delete T cells whose antigen receptors bind too strongly to the complexes of self-peptides and self-MHC molecules presented by thymic cells" " Engagement of the MHC molecule of one of these specialized thymic antigen-presenting cells by the TCR of a thymocyte causes that cell to undergo apoptosis and phagocytosis by macrophages." Mediated by dendritic cells & macrophages. Occurs in the thymus.
Gamma & Delta T cells do not undergo positive in thymus; why don't they need to?
Gamma & delta T-cells. Gamma:Delta T cells don't need to undergo positive selection because they are not MHC restricted.
Percentage of thymocytes survive the process of maturation.
2% of thymocytes survive the maturation process.
Does the thymus play a role in activation of naive T cells? If not, where do the T cells meet their antigen? And which cells present antigen for activation?
The thymus does not play a role in the activation of a T-cell. T cells meet their antigen in secondary lymph nodes. And dendritic cells present the antigen+ MHC 2 for activation.
Where do Dendritic cells settle in the secondary lymphoid tissue?
dendritic cells in the secondary lymphoid tissue settle in the T-cell region
Where does central tolerance for T-cells take place?
Central tolerance for T-cells takes place in the thymus; Bone marrow, thymus (primary lymphoid tissue)
Where does peripheral tolerance for T-cells take place?
Peripheral tolerance for T-cells takes place in the blood; spleen, appendix, tonsils, lymph nodes, peyer's patches (secondary lymphoid tissue)
A regulatory T-cell is a CD-4 or CD-8 T-cell? What transcription factor is unique to T-reg cells? You can look into chapter 8 for this answer if it isn't clear in chapter 7.
A regulatory T- cell is a CD-4 T-cell. A transcription factor unique to T- reg cells is FoxP3.
Stimulating naive T-cells; Dendritic cells; migratory cells
Dendritic cell carries antigen from site of infection, triggering t-cell response, far superior to macrophage and stimulating naive t cell, dendritic cells are migratory cell : carry load off antigen from infection site ->nearest secondary tissue
Naive T cells; endothelial venules (HEVs)
Homing of naïve T cells to secondary lymphoid tissues is determined by cell adhesion molecules. (selectins, vascular addressins , integrins, Ig proteins)
Naïve T-cells leave the blood and enter the cortical region of the lymph node through HEV.
T-cell receptor CCR7 binds chemokines CCL21 and CCL19 on HEV.
Fate of a naive T cell that does not encounter antigen in a secondary lymphoid organ
"In the absence of activation mature, T cells recirculate between the blood, the secondary lymphoid tissues, the lymph and the GALT."
What cells are lymphocytes? What cells Leukocytes?
Lymphocytes: t-cells, b-cells, natural killer cells.
Leukocytes: (another term of white blood cells) Neutrophil, Basophil, Eosinophil (granulocytic cells), Lymphocytes, & Monocytes.
Look up AIRE. What does it stand for, what does it do and what organ in the body would you expect to find it in?
"To extend negative selection to proteins that are specific to one or a few cell types, such as the insulin made only by the beta cells of the pancreas a transcription factor called AIRE."
AIRE is an AutoImmune REgulator which "causes several hundred of these tissue-specific genes to be transcribed by a subpopulation of epithelial cells in the medulla of the thymus."
What are the reasons for the several day delay in a primary response. Infection -> transport to a secondary lymphoid tissue -> antigen processing and presentation -> small intitial # of lymphocytes specific for the antigen -> proliferation and differentiation.
LFA-1, ICAM-1, L-selectin, vasular addressin. Know the homing and cell to cell adhesion slides.
LFA-1(on t-cell) binds to ICAM-1 activated by chemokines it binds to extracellular matrix
L-selectin( on tcell) binds to vascular addressin on surface of HEV venules (cd34 and gycam1)
-ICAM1(epithelial) binds to LFA1
-vascular addressin binds to L-Selectin
-Effector Tcells express CD2 and LFA1 > naïve Tcells
-Effector Tcells have low ICAM-1 and LFA3
Resting CD4 naïve Tcells express L-Selectin, if stops more LFA-1 is expressed.
Activated CD4 Tcells express VLA-4 and have more CD2 (adhesion molecule as LFA-1)
Know the 4 different types of leukocyte adhesion molecules.
The four different types of leukocyte adhesion molecules are selectins (carbohydrate-binding lectins), vascular addressins (contain carbohydrate groups to which selectins bind), integrins, & proteins in the immunoglobulin superfamily.
If a naive T-cell comes into the lymph node from the blood what does it enter through? Figure 8.7
It binds to endothelial cells of HEV (high endothelial venule) and squeeze through vessel wall by diapedesis.
What is S1P? What does it do?
sphingosine 1-phosphate (S1P) is a chemotactic molecule that draws a t-cell out of the lymph node if it hasn't met an antigen.
Know which types of T cells migrate to site of infection after activation and one stays in the secondary lymphoid tissues (lymph node).
TH1 (CD8) cells migrate to the site of infection while TH2 (CD4) cells stay in the secondary lymphoid tissue.
What is CTLA-4? What does it bind to and what is the result of it binding?
CTLA-4 is a B7 receptor expressed by activated T-cells. "B7 binding to CTLA-4 slows down activation and limits cell proliferation." While B7 binding to CD28 activates a T-cell.
What chemokine directs the naive T-cells to the T-cell area to check the dendritic cells MHC molecules? Page 221
Chemokines direct the naive T cell to the T cell area to check dendritic cell MHC CCL=18
What happens when a naive T cell interacts with an antigen presented by a cell that is not a professional antigen presenting cell.
When a naive T cell interacts with an antigen presented by a cell that is not a professional antigen presenting cell, the T cell will become anergic which means it becomes nonreactive.
What does P-APC have that other cells don't have?
What makes P-APC's different from other cells is the presence of B7 co-stimulatory molecules on their surface, it binds to CD28 to activate T-cell or to its antagonist CTLA-4
Is B7 always produces on P-APC's? if not, when do they make it?
No, B7 is not always produced on P-APC's. P-APC's produce B7 only during infections.
Langerhan's cells, what and where are they
"Langerhans' cells (immature dendritic cells) take up the antigen and migrate to a nearby lymph node. Settle in the T-cell areas. Differentiate into mature dendritic cells."
Mature dendritic cells vs. Immature Dendritic cells. What do they do different and what kind of surface molecules do they have (DEC 205 vs DC-SIGN)?
"Mature dendritic cells: Increase expression of B7 co-stimulators, MHC molecules and adhesions molecules like DC-SIGN." Immature dendritic cells: "DEC205 facilitates phagocytosis and pinocytosis of antigens."
T-cell priming/activation (definition)
"T-cell priming occurs when a naive T-cell encounters its specific antigen for the first time and is stimulated to differentiate into an effector cell"
What is macropinocytosis and which cell can did you learn can utilize it? Figure 8.3
"macropinocytosis in where a cell engulfs extracellular fluid." Dendritic cells utilize this.
What does IL-2 do and when is it made?
IL-2 produces an intracellular signal that promotes T-cell proliferation. It is made when a naïve T cell has been activated by the recognition of a peptide.
What is the point of a T-cell priming? What does activation mean? (look at transcription factors that are initiated). What is changed in the cell and what are the major genes produced from that change?
Become an activated or effector cell by encountering antigen, carry out other functions. Can be T-reg, TH1, TH2, or CD8
What are ITAM's? what can bind to them?
ITAM's are immunoreceptor tyrosine-based activation motifs that are sequences in CD3 cytoplasmic tails. Which can bind to cytoplasmic protein tyrosine kinases.(ZAP 70)
What are DAG and IP3, what do they do? What is ZAP 70 and when is it activated (which cell type and when)
-DAG is diacylglycerol and IP3 is inositol triphosphate, these activate the transcription factors NFkB, NFAT and AP-1 which change the pattern of gene expression and control cell division, proliferation and differentiation to effector T-cells.
-ZAP 70 is a cytoplasmic protein tyrosine kinase which binds to the phosophorylated tyrosines on the zeta chain of the T-cell receptor complex. This is activated when T cells are activated by an antigen.
What cell/s is B7 on? What cell is CD28 on? What do they do when they come together?
B7 is found on P-APC's and CD28 are found on T-cells. When they come together they activate a T-cell.
CTL's (CD8 cytotoxic T cells) recognize peptide on MHC 1. Which cells can present with MHC 1?
Almost all cells can present with MHC1. All nucleated cells.
Know the distribution of the 3 different P-APC's in the lymph node
-In the lymph node dendritic cells are in the cortical T-cell areas
-macrophages reside in the cortex & medulla but concentrate in the marginal sinus
-B cells are in the lymphoid follicles.
Definitions of autocrine (same) and paracrine (local).
Autocrine (same) is a secreted cytokine that acts on the cell that produced them. Paracrine (local) is a secreted cytokine that act locally on another cell.
What molecules carry out the effector functions of T cells? (cytokines and cytotoxins)
Cytokines, Chemokines and Cytotoxins
Know the pathways CD8 T cells use to cause apoptosis
i. Know the cytotoxins names
ii. Know Fas and FasL
1. Cytotoxins - perforin and granulysin create pores in the cell membrane, granzymes enter and cleave proteins.Granzymes activate nucleases, RNases and proteases which leads to the breakdown of DNA, RNA and proteins.
2. Cell surface molecules - Fas ligand on CD8 T cell binds to Fas receptor on target cell. Fas:FasL interaction signals for apoptosis
What are VLA-4 and VCAM-1 responsible for? Homing to where?
"VLA-4 binds to the cell adhesion molecule VCAM-1 which is selectively expressed on the endothelium of blood vessels in inflamed tissue." Homing to inflamed tissue.
Can effector T cells be stimulated in the absence of co-stimulatory signal?
Yes they can
IFN-Gamma, CD8 T cells
Secreted by TH1 cells and CD8 T-Cells, they inhibit replication of viruses, activate macrophages, increase processing and presentation of viral antigens by MHC-1
Activation of Macrophages. What is needed? And which cells activate them?
IFN-Gamma and CD40...TH1 cells and CD8 T-Cells secrete IFN-Gamma and CD40L on TH1 cells that interact with CD40R on macrophages. CD8 T-cells do not have CD40L they do express small amounts of bacterial polysaccharides that play the same role as the CD40L
Can Th1 cytokines affect Th2 differentiation and vice-versa?
True...Example- TH2 cytokines can inhibit macrophage activation
What is the only cell that can activate a CD8 T-cell without help?
What are the other ways to get a CD8 T-cell activated other than by a Dendritic cell?
IL-2 which can be secreted by CD4 or CD8 T-Cells
What T cell bias is seen in Tuberculoid vs Lepromtous leprosy? Can you tell which disease state it is by looking at the cytokine profile?
Tuberculoid= TH1 bias, higher amounts of IFN-Gamma cytokines
Lepromatous= TH2 bias, higher amounts of IL-4 cytokines.
What kind (molecules in our book) of signaling would you expect to see JAK's and STAT's in? Figure 8.26
Cytokine Receptor Signaling
Can CD-8 T cells kill more than one cell? Or are they similar to Neutrophils where the can only kill one cell then they die themselves?
Yes, they can kill more than one cell. They attach to the infected cell, release their granules unto the cell, detach and remake their granules. The move on to the next infected cell and do the same thing.
When you see CXCL or CCL would you know right away what is being talked about?
Yes, it's talking about chemokines.
TH1 cells activate ____________. TH2 cells activate _________.
Macrophages & B-Cells
ALPS is caused by what?
ALPS is caused by the lack of functional Fas molecules which therefore cannot control the size of their lymphocyte population nor remove autoimmune cells.
Look at what an activated Th1 cell can do (figure 8.35) and what cytokines it can secrete.
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