I8 Flashcards
Where does T cell activation occur?
exclusively in the secondary lymphoid tissues.
Why does T cell activation only occur in secondary lymphoid tissue?
This is due to that fact that secondary lymphoid tissues are the only place where there is enough contact between APCs and naïve T cells…remember, there may only be a single T cell in the entire repertoire that has specificity for any particular peptide determinant.
What two signals are required for T cell activation?
A T cell must recognize its cognate peptide determinant (signal 1) and then receive the costimulatory signal that consist of B7 expressed by the APC binding to CD28 expressed by the T cell (signal 2).
T or F. Naïve T cells can only be activated by professional APCs. Why or why not?
T, because they are the only cell types that express B7.
How do T cells move into secondary lymphoid tissue from the bloodstream?
Naïve T cells move into secondary lymphoid tissues by transmigration between the endothelial cells of what are known as high endothelial venules or HEVs. This process is mediated by adhesion molecule interactions.Once T cells occupy a secondary lymphoid tissue, they sample peptide:MHC complexes on the surface of APCs.`
What happens to naive T cells that never encounter their cognate determinant in the secondary lymphoid tissue?
they will eventually leave the secondary lymphoid tissue via the efferent lymph and travel to another secondary lymphoid tissue.
What happens to naive T cells that DO encounter their cognate determinant in the secondary lymphoid tissue?
If a naïve T cell encounters its cognate peptide:MHC complex and then receives the needed co-stimulation, the T cell begins to proliferate. The daughter cells then differentiate either into effector cells or memory cells.
What are the 4 classes of cell-surface adhesion molecules that are expressed on the surface of host cells (both immune cells and non-immune cells)?
1) Selectins2) Mucin-like vascular addressins3) Integrins4) Immunoglobulin superfamily members
What are selectins?
Lectins that bind to the mucin-like vascular addressins (e.g. CD34, GlyCAM-1, PECAM-1 (CD31))
What are Integrins?
lymphocyte function associated antigen (LFA-1), VLA-6, alpha-V-beta-3Integrins bind to the immunoglobulin superfamily members.
What are the members of the immunoglobulin superfamily?
intracellular adhesion molecules (ICAMs), CD2, LFA-3, VCAM-1these bind to integrins
Remember that all cell-to-cell interactions are initiated by adhesion molecule interactions and that a genetic deficiency of expression of an adhesion molecule could have very important implications for the immune status of the patient.
Remember that all cell-to-cell interactions are initiated by adhesion molecule interactions and that a genetic deficiency of expression of an adhesion molecule could have very important implications for the immune status of the patient.
How is the process of naïve T cells entering secondary lymphoid tissue through high endothelial venules mediated by adhesion molecule interactions?
L-selectin expressed on the surface of naïve T cells are able to bind to addressins (such as CD34) that are expressed on the surface of HEVs. This initiates the process of T cell migration from the vasculature into the secondary lymphoid tissue
L-selectin also has affinity for what other addressin besides CD34?
GlyCAM-1, which is also known as sulfated sialyl-Lewis.
Describe the entire process of T cell extravasion
- Circulating T cell enter the HEV in the lymphoid tissue2. Binding of L-selectin on the T cell surface to GlyCAM-1 and CD34 allow rolling interaction3. Once the T cell is closely associated with the HEV surface, other interactions can occur. Chemokines that are bound to the vascular endothelium can be recognized by chemokine receptors on the surface of the T cell. This results in signaling to the nucleus of the T cell, resulting in activation of the integrins known as LFA-1 on the surface of the T cell.4. Activated LFA-1 binds tightly to ICAM-15. Diapedesis- lymphocyte leaves blood and enters node
LFA-1 on T cells is important for the T cell’s ability to interact closely with APCs. How?
LFA-1 on T cells is able to bind to ICAM-1 expressed on the surface of APCs. Without this interaction, T cells would not be associated closely enough with APC for MHC:peptide complex sampling by the TCR.
Once a T cell has differentiated into an effector cell, how can it be encouraged to enter into inflammatory sites?
because it now expresses the integrin known as VLA-4 that can bind to VCAM-1 that is expressed on activated endothelial cells (they become activated when they are in an inflamed tissue).
What is E-selectin?
is an adhesion molecule from the selectin family that is expressed on vascular endothelial cells that binds to addressins expressed by a variety of leukocytes, including the phagocytes (neutrophils and macrophages), effector T cells, NK cells, and eosinophils.E selectins: Every new kid eventually takes nuestro money
Expression of E-selectin on vascular endothelial cells is stimulated by the cytokines ___ and ____.
TNF-alpha and IL-1Once E-selectin is expressed on the surface of vascular endothelial cells, addressins expressed on the surface of immune cells bind to E-selectin, initiating the diapedesis process and resulting in accumulation of leukocytes in the inflamed tissue.You may need to know that many tumor cells also express E-selectin ligands, so E-selectin is indirectly involved in tumor metastasis.
All 3 APCs express what important molecule on their surface?
Costimulator molecule (B7). However, expression of B7 by these cell types is conditional.
When do dendritic cells express B7?
only express B7 once they have moved into secondary lymphoid tissues
When do macrophages and B cells express B7?
Both macrophages and B cells express B7 in an inducible manner. If they encounter ligands that bind to their pattern recognition receptors (indicating that there is an infection and an immune response is needed), they will upregulate B7 expression.
Which APC is the best for presentation of VIRAL determinants? Why?
dendritic cells are the most important APC for presentation of viral determinants.DCs are easily infected by viruses and once infected they are very efficient antigen presenting cells.
Which APC is the best for presentation of BACTERIAL determinants? Why?
Macrophages are the most important APC for presentation of bacterial determinants because they have many surface PRRs that recognize bacterial surface determinants.B cells can present anything that binds to their surface immunoglobulin component of the B cell receptor. You should be aware that B cells take up antigen primarily via their surface Ig. Once the Ig binds to its cognate determinant, the entire complex is endocytosed and any protein components are processed and presented on MHC molecules (primarily MHC class II).Please be aware that each of these cell types can present antigens derived from any type of pathogen, despite the rules of thumb that I just mentioned.
What is the immature form of dendritic cells?
Langerhans’s cells. These immature forms dendritic cells populate the tissues underlying all epithelial layers of the body.
T or F. Langerhans’s cells express B7 molecules on their surface
F. In this form, they do not express B7 molecules and cannot present antigen productively to naïve T cells, but they are very efficient at uptake of antigens. They do express MHC I and II here.
What happens when Langerhans cells encounter pathogen antigens?
When they encounter an invading pathogen, they take up antigen, some of which engages PRRs, signaling to the cell that an infection is ongoing and an immune response is needed. The Langerhans’s cell then travels via the lymphatics to the draining secondary lymphoid tissue
What happens once the Langerhans’s cell reaches the secondary lymphoid tissue?
It matures into a fully functional APC. The DC then begins to express high levels of B7 and can very efficiently present antigens to naïve T cells that have specificity for peptides presented on MHC molecules on the DC’s surface.They also have mechanisms for transfer of antigens to other DCs already in the tissue
It is critical that you understand where T cell activation occurs…it always occurs in secondary lymphoid tissues, and it is dependent on the T cell receiving B7 co-stimulation that can only be supplied by a professional APC.
It is critical that you understand where T cell activation occurs…it always occurs in secondary lymphoid tissues, and it is dependent on the T cell receiving B7 co-stimulation that can only be supplied by a professional APC.
What is the (very) general basis of cross-presentation mechanisms?
The MHC class I pathway and how peptides derived from proteins that were in the cytoplasm of the cell are trafficked into the MHC class I pathway. I have also talked about the MHC class II pathway and how peptide derived from proteins taken up from the extracellular milieu are presented primarily through the MHC class II pathway. However, it is important for you to recognize that some peptides derived from intracellular pathogens will be presented through the MHC class II pathway and some peptides derived from extracellular pathogens will be presented via the MHC class I pathway. The mechanisms are complex.. don’t need to know for Step 1
What type of MHC molecule and CD molecule would usually be used in the presentation of extracellular bacteria?
MHC class II and CD4
What type of MHC molecule and CD molecule would usually be used in the presentation of viruses?
MHC class I and CD8 (think intracellular)
What kinds of surface receptors can be seen on the surface of an immature dendritic cell (Langerhans cell)?
These cells express both MHC class I and MHC class II and they express several adhesion molecules (LFA-1, ICAM-1, and LFA-3 or CD58). Another surface marker that is shown here is complement receptor 4 that allows DCs to recognize antibody-opsonized foreign materials, facilitating uptake for processing and presentation. There are also a couple of surface pattern recognition receptors indicated (DC-SIGN and DEC 205). There are many others that are not included here.I do not expect you to memorize any of these, but instead want you to remember that adhesion molecules are critical to the function of all immune cells, that the professional antigen presenting cells all express both MHC class I and MHC class II as well as B7 molecules, but that the expression level of each of these is increased dramatically when the APC has determined that an immune response is needed (due to PRR engagement). As you see here, this immature tissue DC does not express B7 molecules.
What differences in the types/amount of surface receptors can be seen on the surface of a mature dendritic cell after it has made its way into a lymphoid tissue?
A mature DC moves into a secondary lymphoid tissue because it detected some type of pathogenic insult. The most important differences that you should recognize are: (1) mature DCs express high levels of B7 molecules on their surface, enabling them to productively present peptide determinants to naïve T cells, and (2) they upregulate expression of both MHC class I and MHC class II so that they can more efficiently present peptides to T cells.
What is DC-CK?
Mature DCs produce DC-CK, a chemotactic factor for naïve T cells. This increases the rate of T cell sampling of the MHC:peptide complexes on the surface of the DC.
How do B cell take up antigens for processing and presentation to T cells?
Each B cell expresses many copies of its BCR, and each copy has an identical immunoglobulin component that can recognize a specific antigenic determinant. If the B cell encounters its cognate determinant, the BCR:antigen complex is endocytosed and the protein components of that entire complex are proteolytically processed. Peptides derived from that processing are then loaded onto MHC molecules (primarily MHC class II) that are then transported to the surface of the B cell for display.
