Immuno 6: T Cell Diversity and Development Flashcards
What are the two type of T cell receptors?
alpha-beta (more common)
gamma-delta
At the extreme end of the ____ region of each TCR chain is a hinge-like region followed by a ____ region and a short tail that extends into the cell ____.
carboxyterminal; transmembrane; cytoplasm
What is the mechanism that generates a huge T cell receptor repertoire?
somatic recombination with cassette genes
With what do T cells recognize specific antigens?
with their TCR
In what tissue are the less common gamma-delta TCRs found?
mucosal epithelium
γ/δ T cells have a limited TCR repertoire and it is believed that they primarily recognize what kind of antigenic determinants?
non-protein antigenic determinants
Where do α/β and γ/δ T cells mature?
α/β = thymus γ/δ = extrathymically
True or false: γ/δ T cells only recognize antigens bound to MHC class molecules.
False. γ/δ T cells are not MHC restricted in their recognition of antigen. However, α/β TCRs recognize peptide antigens only when presented in context with the MHC proteins.
What are the two distinct populations of α/β T cells?
CD4+ and CD8+
Generally speaking, what are CD4 and CD8 proteins?
they are proteins expressed on the surface of T cells that serve as co-receptors for the TCR to facilitate interaction with the MHC complex on antigen-presenting cells
CD4 is present on ____ T cells.
CD8 is present on ____ T cells.
helper; killer
CD4-associated TCRs binds MHC Class ____.
CD8-associated TCRs binds MHC Class ____.
CD4-associated TCRs - MHC II
CD8-associated TCRs - MHC I
What are the functions of CD4-associated TCRs?
bind MHC class II; produce cytokines; help B cells; stimulate cells of the innate immune system
What is the function of CD8?
to kill cells that are presenting their cognate peptide antigen using the MHC Class I molecule (i.e., intracellular infection)
Name 6 types of surface markers expressed on the surfaces of T cells.
- T Cell receptors
- CD4/CD8
- CD3
- Accessory molecules
- Adhesion molecules
- Lymphokine receptors
What is the signal transduction complex for the T cell receptor, and what does it use to cause intracellular cascades??
CD3; uses tyrosine kinases to cause phosphorylation cascades and other events leading to T cell activation
Each of the TCR chains has a single ___ domain and a single ___ domain.
variable; immunoglobulin
Are γ/δ a component of the acquired immune response?
no - they appear to be a primitive cell type
Unlike the α/β T cells, the γ/δ T cells are usually double negative. What does this mean?
α/β cells express CD4+/CD8+ whereas γ/δ T cells express CD4-/CD8-
What are ITAMs?
immunoreceptor tyrosine-based activation motifs; located on cytoplasmic domains of CD3 complex, and are critical for initiating the signal cascade
True or false: a single mature α or β T cell can express CD4, CD8, or both on its surface.
False - can express one or the other, but NOT both
CD28 is a molecule that binds to the co-stimulator molecule, known as ___, expressed on antigen-presenting cells that have encountered pathogens.
B7
Fas ligand (FasL) is a homotrimeric molecule that can bind what on target cells? Binding then results in signaling that initiates what?
binds 3 copies of Fas on target cells; binding results in signaling that can then initiate programmed cell death of the target cell
What do adhesion molecules do? (in the context of immune cells)
facilitate the cell-to-cell interactions between immune cells
What are T cell precursors called?
thymocytes
Where do thymocytes develop?
thymus
What are the 2 regions of the thymus, and what primary cell types are located in each?
cortex: - cortical epithelial cells - thymocytes - macrophages (few) medulla: - medullary epithelial cells - dendritic cells - macrophages - developing, near-mature thymocytes - Hassel's corpuscles
The junction between the cortex and medulla of thymus is called the corticomedullary junction. What important step in thymocyte development happens here?
positive selection of the cells that bind MHC Class I or II, and differentiation into CD8+ or CD4+ T cells; this process involves up-regulation of the CD protein that binds with greater affinity to its MHC
Tingible body macrophages play a large role in what part of the thymus? What do they do there, and what causes their unique staining pattern?
in the cortex: they phagocytize and remove dead thymocytes; the large amount of chromatin taken up from eating the thymocytes causes their unique staining pattern
Once the T cell repertoire is formed during normal development, are new T cells required to sustain T cell mediated immunity?
No - thus the thymus shrinks after puberty
What is the process of T cell ontogeny in the thymus?
- Thymocytes arrive in cortex, proliferate
- Positive selection: those that can’t bind self-MHC undergo apoptosis.
- Survivors move to medulla where negative selection occurs: those that bind too tightly to self-MHC:self peptide (self-antigens) will undergo apoptosis
All thymocytes enter the thymus as CD4/CD8 positive or negative?
negative
Double positive CD4+/CD8+ T cells that survive positive selection differentiate to ____ ____ T cells.
single positive, by up or down regulating the other, non-preferred TCR
CD4-/CD8+ T cells bind which MHC class?
Class I - because they are now known as CD8+ cells
CD4+/CD8- T cells bind which MHC class?
Class II - because they are now known as CD4+ cells
Where do the self-peptides come from in thymus for use in the negative selection process of maturing T cells?
autoimmune regulator (AIRE) is a TF that produces the expression of hundreds of host-tissue specific peptides in a subset of epithelial cells in the thymic medulla where they are uptaken by medullary APCs for presentation with MHC molecules
What happens if a patient lacks a functional AIRE gene?
they’ll have broad spectrum autoimmune disease
In TCR genes, the coding region for the variable region of the ____ chain is produced by rearrangement of V and J gene segments. (analogous to light chain rearrangement)
alpha
In TCR genes, the coding region for the variable region of the ____ chain is produced by rearrangement of V, J, and D gene segments. (analogous to heavy chain rearrangement)
beta
How does a T cell become either alpha-beta or gamma-delta?
depend on which chain is the first to rearrange:
- start rearranging beta, gamma delta
- if either gamma or delta is successful first, the T cell will become gamma-delta
- if beta wins, it will become alpha-beta
What is the utility of the pTalpha chain?
it’s an invariant chain that serves as a surrogate alpha chain to associate with the beta chain and create the pre-T cell receptor complex while awaiting the alpha chain to finish rearranging; without a friend the beta chain is too unstable and will die of loneliness
When would gamma-delta rearrangement cease if the T cell is going to become an alpha-beta TCR cell?
when the pre-TCR complex is formed using a successful beta chain and a pTalpha chain; this happens before alpha chain rearrangement begins
Why should we remember Hassall’s corpuscles today?
this cell type may play a critical role in the development of T regulatory cells, which have an important role in preventing autoimmune disease, by producing a cytokine that drives some self-reactive T cells to differentiate into T regs instead of apoptosing
Where do mature naive T cells hang out?
secondary lymphoid tissue
What chromosomes are TCR alpha and beta chain genes located on?
alpha = 14 beta = 6
As was the case for somatic recombination of the B cell immunoglobulin genes, somatic recombination of the TCR Ig genes is catalyzed by ___ and ___.
RAG-1 and RAG-2
Genetic deficiency of one or both RAG genes would result in what?
an almost TOTAL lack of B and T cells, and SCID #suckstoSCID
A deficiency of TdT will result in ____ ____ of both the T cell and B cell repertoire because there will be no ____ ____ of the beta and heavy chain, respectively.
reduced diversity; junctional diversity
Based on the ____ ____ of the T cell tumors, it can be determined at what point in the development of the T cell that the neoplastic event took place.
surface phenotype
Common acute lymphoblastic leukemia (C-ALL or B-ALL): the neoplastic event for this tumor type took place in what cell?
a lymphoid progenitor cell
These tumor cells arise from thymic stromal cells, therefore the do not express any lymphocyte-specific surface markers.
Thymoma
Acute lymphoblastic leukemia (T-ALL): neoplastic event took place in a ____, as evidenced by its surface expression of ____.
thymocyte; CD1
Adult T cell leukemia; chronic lymphocytic leukemia (CLL); or T prolymphocytic leukemia (TPLL): the neoplastic event took place in a T cell that was at what stage of development, and how is that known?
nearing or was a mature T cell; known because there is already a complete TCR and it’s a single positive cell
CD34 is a ____ cell surface marker.
stem cell (hemopoietic progenitor)
How do self-reactive T cells sometimes get through positive selection?
because all MHC molecules must be loaded with a peptide (otherwise they get degraded), there’s a chance that a TCR could end up passing positive selection because it has strong affinity for the loaded peptide, which would appear in this process as being affinity for the MHC molecule.
When pathogens are presented to T cells in a lymph node, which protein mediates T cell receptor signaling?
CD3
*Note: the TCR will bind the MHC:antigen. Then CD3 will then mediate the signaling pathway.
Which T cell surface marker has affinity for B7 co-stimulator molecules located on APCs?
CD28. This reaction is critical because B7 is what makes a cell a “professional antigen presenting” cell.
Immature thymocytes generated in the bone marrow migrate to the thymus to undergo their development. What compartment of the thymus do they initially populate once they arrive?
cortex
What happens to thymocytes once they reach the thymic cortex, prior to any repertoire selection?
- proliferate as double positive CD4/CD8-associated TCR cells; also express CD3
- beta, gamma, delta chain rearrangement
- gamma/delta rearrangement occurs first, that cell leaves the thymus to mature extrathymically. If beta rearrangement occurs first it will be an alpha-beta cell
- beta pairs with pTalpha chain (pre-TCR) until alpha chain is generated
Positive selection is driven by the TCR’s affinity for what?
MHC class of molecule
True or false: TCR selection of CD4+ or CD8+ thymocytes is complete by time the T cells arrive at the medulla.
true - they arrive at the medulla as single-positive TCRs already
What’s a good reason that self-reactive T cells make it through negative selection and leave the thymus as mature members of the T cell repertoire?
there are so many self-peptides they can’t all be expressed
If a patient has few B and T cells due to an inherited genetic deficiency, a non-sense mutation of what enzyme dysfunction would be suspected?
RAG-1 and RAG-2, because lack of these is what would cause lack of B cell antibodies and T cell receptors. TDT, while involved, would simply decrease the variety of the repertoire.
