T Cells of Adaptive Immunity Flashcards
What are the two main weapons of adaptive immunity?
Antibodies and T cells
What do T cells defend against?
T cells are the main defense against viral infections and bacterial pathogens that cause intracellular infections (e.g., Mycobacterium tuberculosis).
What is TCR?
The T cell receptor (TCR) is a membrane-bound protein composed of two different polypeptides known as the α chain and the β chain.
The two chains are joined together by a disulfide bond.
There are no secreted forms of the TCR.
Expression of the TCR involves rearrangement of TCR “gene segments” to form a complete gene. This happens for both chains. Therefore, each T cell has its own “version” of the TCR and thus has unique antigen specificity.
What forms the antigen-binding site on a TCR molecule?
- The TCR α and β chains expressed at the cell surface each have one variable (V) region and one constant (C) region.
- The Vα and Vβ chains regions combine to form the antigen-binding site.
- There is only one antigen-binding site per TCR molecule.
A single, mature T cell will have approximately 30,000 identical copies of the TCR on its cell surface.
What does the TCR complex of a mature T cell consist of?
An antigen-binding portion that is comprised of the TCR α and β chains, plus an associated signaling subunit (CD3 complex) and accessory proteins (either CD4 or CD8, but not both).
What does the TCR antigen-binding subunit recognise? What doesn’t it recognise?
Peptides that are bound to MHC proteins. It does not recognise native, intact (unprocessed) antigens.
What causes proliferation of a T cell?
The signaling subunit (CD3) of the TCR sends signals to the inside of the T cell that activates it and causes it to proliferate.
What defines the effector function of a T cell?
The co-receptors CD4 and CD8.
Where are CD4 and CD8 found?
CD4 is found on T helper cells whereas CD8 is found on cytotoxic T cells.
Where do CD4 and CD8 bind?
CD4 and CD8 bind to the MHC proteins on the antigen-presenting cell, but not at the site involved in peptide binding.
What does contact between CD4 or CD8 and MHC proteins increase?
Increases the affinity of interaction between the T cell and the antigen-presenting cell.
What does the CD4 co-receptor recognize?
A conserved region (not involved in peptide binding) of MHC class II proteins.
What does the CD8 co-receptor recognize?
A conserved region (not involved in peptide binding) of MHC class I proteins.
What are CD3 proteins and how are they activated?
The CD3 proteins are signaling proteins that are activated once the TCR has recognized antigen.
What are CLPs?
Some progeny of the HSCs start to “specialise” into common lymphoid progenitors (CLPs) that can further differentiate into T cell precursors that leave the bone marrow environment and travel to the thymus to complete their maturation.
What are T cell precursors?
Thymocytes
How do thymocytes proliferate?
The thymocytes proliferate and differentiate along developmental pathways that eventually generate functionally distinct T cell populations.
Do T cell precursors express a TCR?
T cell precursors (known as thymocytes) do not express a TCR.
What must a developing thymocyte do in the thymus in order to survive?
Begin to express a TCR on its cell surface in order to survive
How are major stages of developing thymocytes tracked?
By changes in expression of the TCR, as well as of CD4, CD8, and other proteins.
What screening processes are thymocytes expressing TCRs subjected to?
Positive-selection and negative-selection.
What mediates positive selection?
Positive selection is mediated by thymic cortical epithelial cells.
What mediates negative selection?
Negative selection is mediated by bone marrow derived macrophages and dendritic cells, and medullary thymic epithelial cells (mTEC).
What is a double positive thymocyte?
DP = double positive, a immature thymocyte that is expressing both CD4 and CD8.
Where do T cell precursors that leave the bone marrow travel for maturation?
T cell precursors that leave the bone marrow environment and travel to the thymus to complete their maturation.
Which thymocytes are permitted to mature during positive selection?
Only thymocytes that have a TCR capable of weakly binding to MHC proteins of thymic cortical epithelial cells (displaying self-peptides) are permitted to mature.
What does positive selection ensure?
When a thymocyte matures into a T cell, its TCR will be able to bind to MHC proteins displaying foreign peptides.
What happens to thymocytes that have a TCR that cannot bind to MHC proteins?
Thymocytes that have a TCR that cannot bind to MHC proteins (displaying self-peptides) are not provided with survival signals and die of neglect
How many “rounds” of negative selection are thymocytes subjected to following positive selection, and what mediates each one?
Two total.
First is mediated by bone marrow derived macrophages and dendritic cells.
Second is by thymic medullary epithelial cells.
Which thymocytes are signalled to undergo apoptosis during negative selection?
Thymocytes that have TCRs that bind to MHC and self-peptide with high affinity receive a signal to undergo apoptosis.
What does negative selection test for?
Self-tolerance: if the recognition of MHC with self-peptide activated the T cells, then autoimmune disease could result.
What is the consequence of thymic selection?
Only a small fraction (less than 5%) of thymocytes develop into mature T cells.
Which thymocytes are permitted to mature into functional T cells?
Only thymocytes that have TCRs that bind to MHC (displaying self-peptides) with weak affinity.
Where do functional T cells migrate after they leave the thymus?
Peripheral lymphoid organs (lymph nodes and spleen)
T cells that survived positive and negative selection can be potentially activated by […] ?
MHC displaying foreign peptides because the TCR would recognise the foreign peptide displayed by the MHC protein with higher affinity.
What does negative selection ensure?
Ensures mature T cells are not self-reactive.
How can negative selection be achieved against antigens that are normally expressed outside of the thymus?
More recent studies have shown that there is an autoimmune regulator (AIRE) gene that promotes the expression of a wide variety of tissue antigens, including those not typically associated with the thymus (the AIRE gene encodes a transcription factor).
This second round of negative selection is by thymic medullary epithelial cells.
Production of what type of cell is involved in regulating the activity of self-reactive T cells that have somehow escaped negative selection?
A special type of T cell called a T regulatory (Treg) cell.
What is development of Treg cells in the thymus throught to be dependent on?
Relatively high affinity interactions with self-antigens
How do Treg cells generated in the thymus differ from conventional T cells?
By expressing high levels of CD25 (one part of the receptor for IL-2).
Can Treg cells be developed outside of the thymus?
There are also mechanisms for the development of different types of Treg cells outside of the thymus, and these cells are not necessarily specific for self-antigens.
How are Treg cells unique?
They prevent conventional T cells from mounting immune responses.
The mechanisms by which they suppress these responses are currently a very active area of research.
What is the antigen recognised by the T cell receptors of mature CTLs and T helper cells?
T-cell receptors do not recognize antigen in its native state, as do the immunoglobulin receptors of B cells, but recognize a composite ligand of a peptide antigen bound to an MHC molecule.
Where does T cell selection take place, and what does it select for?
In the thymus and selects for TCRs that work (positive selection), but are not self-reactive (negative selection).
What are CTLs and what do they do?
Killer T cells; they express CD8 and recognise MHC class I.
What is the function of T helper cells?
- Help other immune cells
- express CD4
- recognise MHC class II
What defines the structure and function of helper T cells and of cytotoxic T cells?
The co-receptors CD4 and CD8 define the effector function of the T cell:
- CD4 is found on T helper cells
- CD8 is found on cytotoxic T cells
T cell receptors (TCRs) are found exclusively on T cells.
True or false?
True
Cytotoxic T cells express the CD8 protein as a co-receptor.
True or false?
True
T cells undergo immune selection. T cells that gain access to the circulation have been screened for the ability to recognize MHC proteins and against strong reactions to self-antigens.
True or false?
True
Self-reactive T cells are eliminated during the development of tolerance in the immune system.
True or false?
True
The T cell receptor is made of one copy of the β chain and one copy of the α chain.
True or false?
True
CD3 is the signalling component of the T cell receptor complex.
True or false?
True
A mature T cell has both CD4 and CD8 proteins on the cell surface.
True or false?
False
A T cell receptor complex in a mature T cell has one copy of the β chain, one copy of the α chain, the CD3 protein, and the CD4 or CD8 co-receptor.
True or false?
True
The TCR of a thymocyte must be able to interact with an MHC protein in order for the thymocyte to escape apoptosis.
True or false?
True
If the TCR of a thymocyte binds MHC very tightly, it will be positively selected and retained.
True or false?
True
Almost all thymocytes pass positively selection, very few however, pass negative selection.
True or false?
False
Treg cells help to control the self-reactivity of T cells that have somehow escaped negative selection.
True or false?
True
The AIRE gene encodes a transcription factor.
True or false?
True
The AIRE gene product allows medullary thymic epithelial cells to display peptides derived from proteins normally expressed by cell types outside of the thymus environment.
True or false?
True
Where are precursor T cells derived?
Precursor T cells are derived from lymphoid precursor cells in the bone marrow - they migrate to the thymus to continue their maturation and start to express the TCR and other proteins.
What are the two main types of effector T cells?
CD4 T helper cells
CD8 T killer cells
Which peptides do CD4 T helper cells recognize?
peptides presented on MHC class II proteins
Which peptides do CD8 T killer cells (or cytotoxic T lymphocytes, CTL) recognize?
peptides presented on MHC class I proteins
What does the co-receptor CD4 or CD8 do?
strengthens the interaction between the antigen-presenting cell and T helper cell
What does αβ TCR recognize in antigen recognition?
Aa complex of the MHC and peptide
What is the role of CD3 (γε, δε, ζζ subunits)?
Relays a signal to nucleus that TCR has been engaged, triggers new gene expression
How does CD3 signal?
CD3 and p56lck: p56lck is a kinase - adds phosphate groups to proteins (from ATP)
What determines how a T cell matures?
The TCRs interaction with the MHC determines whether it matures into a CTL or T helper cell.
What is the goal of positive selection of developing T cells?
Why is this important?
What does positive selection depend on?
What does positive selection select for?
Goal: Identify developing T cells that can bind to MHC proteins
Importance: APCs present peptides in complex with MHC; if T cell can’t interact with MHC, it can’t be activated.
Depends on: low affinity interactions between TCR and MHC + selfpeptide.
Selects for: T cells that are be potentially useful for developing immune responses against foreign antigens, particularly pathogens.
What cells mediate positive selection of developing thymocytes?
The thymic cortical epithelial cells
What is the goal of negative selection of developing T cells?
What is the importance?
What does negative selection depend on?
Goal: Identify developing T cells that bind MHC + self-peptide a little too tight.
Importance: T cells that bind MHC + self-peptide too tightly may be activated in the lymph node/spleen; could result in autoimmune disease.
Depends on: high affinity interactions between TCR and MHC + selfpeptide - these cells must be eliminated to maintain tolerance to self.
What cells mediate negative selection in the thymus?
Bone marrow derived antigen-presenting cells
How many candidate thymocytes actually pass positive and negative selection?
Less than 5% of candidate thymocytes actually pass positive and negative selection – most fail at the positive selection stage.
What is the goal of positive and negative selection of thymocytes?
Get rid of the useless – those T cells that have TCRs that can’t interact with MHC because these cells could never be activated.
Get rid of the dangerous – those T cells that have TCRs that recognize MHC + self peptide strong enough to activate the T cell.
Keep only the ones that are potentially useful.
They might be able to recognize MHC and pathogen peptide with sufficiently high affinity to be activated.
Where is the AIRE gene expressed?
The autoimmune regulator (AIRE) gene is expressed in thymic medullary epithelial cells.
What does the AIRE gene do?
The AIRE gene product is involved in transcriptional regulation - it allows the expression of a wide variety of tissue-specific antigens in the thymus.
AIRE allows for negative selection against tissue specific antigens
(i.e., so you don’t have T cells that amack your heart, kidney, insulin producing islet cells)
What happens to T cells with TCRs that cannot interact with MHC?
T cells with TCRs that cannot interact with MHC would be useless: these cells get no survival signal - default pathway is apoptosis.
What happens to T cells with TCRs that interact with MHC and self-peptide strongly?
T cells with TCRs that interact with MHC and self-peptide strongly are dangerous: these cells are signaled to undergo apoptosis (programmed cell death).
What happens to T cells with TCRs that interact with MCH and self-peptide weakly?
Only T cells with TCRs that interact with MHC and self-peptide weakly are allowed to mature: these cells may be able to recognize MHC and pathogen peptide with sufficiently high affinity to be activated.
How are Treg cells different?
These T cells are “different” – somehow encouraged to be self-reactive and are not negatively selected during T cell development in the thymus.
What is IL-10?
a “calming” anti-inflammatory cytokine
What is the function of T regulatory cells?
- Shuts down self-reactive cells in the periphery: - prevents conventional T cells from mounting immune responses.
- “Resets” anergic cells: - so that they may be activated during infection. - gives cells a ‘second chance’
A deficiency in Tregs is correlated with an increased incidence of autoimmune disease.
Tregs are upregulated in some instances of cancer – shuts off the immune response to tumour cells.
What is an anergic lymphocyte?
Lymphocytes are said to be anergic when they fail to respond to their specific antigen.
What medical condition does the nude mouse model for?
How is this condition treated?
DiGeorge syndrome - several genetic mutations can cause this condition.
Patients will have hair, but may have other serious health problems: e.g., heart defects, seizures, hypocalcemia.
Treatment - transplantation of a thymus graft
