Biology of the T cell

Question 1

describe the composition of TCR

Answer 1

two peptide chains (dimer) joined by a disulfide bond in the constant region

Question 2

how can TCR recognize linear peptides presented through an MHC molecule (MHC restriction)?

Answer 2

TCR has a single binding site (monovalent)

Question 3

what happens when the T cell is activated via TCR?

Answer 3

the TCR remains attached to the cell membrane and the variable regions of the TCR remain unaltered even following T cell clonal expansion or replication

Question 4

when does α,β TCR arise?

Answer 4

during T cell differentiation in the thymus

Question 5

what interaction defines the structural conformation of the linear antigen epitope binding site?

Answer 5

complementarity-determining regions (CDR1, CDR2 and CD3) and are found on the variable regions of both chain

Question 6

true or false: each α and β chain possess a CDR1, 2, and 3 region

Answer 6

true

Question 7

true or false: the TCR has a cytoplasmic domain, unlike the BCR

Answer 7

true

Question 8

what does initial activation of the T cell require?

Answer 8

requires the binding of the TCR to the linear peptide present by MHC, which activates to adjacent cell surface proteins CD3 and CD247 collectively called the T cell receptor complex

Question 9

Both ___ and _______ function signal transduction molecules which means that they amplify the activation signal, but do not directly bind Ag.

Answer 9

CD3 and CD247

Question 10

what does CD3 function as?

Answer 10

• signal transduction molecule
• chaperone for translocation of TCR to cell membrane surface

Question 11

what are the key mediators of T cell activation?

Answer 11

immunoreceptor tyrosine-based activation motif (ITAMS) (of CD247)

Question 12

how are CD4 and CD8 cell surface proteins in close association with the TCR?

Answer 12

during T cell differentiation that they are up regulated in expression and once a T cell completes differentiation the naïve T cell expresses either a CD4 or CD8 cell surface molecule to denote it as a helper T cell or cytotoxic T cell. It retains this phenotype through out its life span as well as conveying it to its clones should it replicate

Question 13

CD4 and CD8 have been identified on what other leukocytes?

Answer 13

(CD4 on monocytes, macrophages and dendritic cells; CD8 on dendritic and NK
cells)

Question 14

once the T cell is activated via linear antigen peptide recognition via MHC, the CD4 or CD8 binds to the MHC portion and functions as an ____________________ to strengthen the binding.

Answer 14

adhesion molecule

Question 15

the adhesion molecule binding to the MHC can also serve as an additional ___________________
in that it can lower the threshold for T cell activation

Answer 15

signal transduction

Question 16

what can be used to measure the percent of CD4+ and CD8+ peripheral blood leukocytes?

Answer 16

flow cytometry

Question 17

what were shown to be the major targets for viral destruction resulting in a severe compromised cell-mediated immunity in patients with AIDS?

Answer 17

CD4 T cells

Question 18

what are the secondary signals for full T cell activation for naïve T cells? what mechanism do they use?

Answer 18

CD28 receptor family on T cells and the
B7 ligand family on APCs

receptor is the lock and the ligand the key

Question 19

Binding of CD28, which is the only B7 receptor constitutively expressed on naïve T cells, by the
either B7 ligand CD80 (B7.1) or CD86 (B7.2) fully activates the naïve T cell to synthesize and
release a _____________, a promotor of T cell replication

Answer 19

cytokine IL-2

Question 20

what happens if an activated naïve T cell fails to
receive a secondary signal through CD28?

Answer 20

becomes anergic (shuts down)

Question 21

what is downregulated once a T cell becomes activated as effector T cell? what becomes upregulated?

Answer 21

CD28 down
CD152 (CTLA-4) up

Question 22

The binding of CD152 by either CD80 or CD86
provides a __________ signal to the effector T cell shutting it down

Answer 22

negative

Question 23

what is another important signaling pair in that it can enhance the CD28-CD80/CD86 signal transduction, but also is important in isotype-switching and somatic hypermutations in B cells?

Answer 23

CD40-CD40 Ligand

Question 24

Similar to events post B cell activation, T cells upon activation migrate out of the lymphoid
tissue to other tissue sites in the host. what signals from what two molecules must happen to accomplish this?

Answer 24

• homing molecules
• adhesion molecules

Question 25

adhesion molecule info

Answer 25

may also play a role in facilitating TCR-MHC interactions by slowing their migration through the lymphatic tissues to allow for the potential interaction. Some of the well characterized adhesion molecules include CD2 which binds to CD58(LFA-3) on APCs (i.e. macrophages); CD11aCD18 (LFA-1) which binds to CD54(ICAM-1) on APCs and endothelial cells plus some other ligands; CD50 (ICAM-3) which binds to LFA-1 on APCs.

Question 26

homing molecule info

Answer 26

play an important role in facilitating TCR-MHC interaction as well as mobilizing the T cells post activation to other tissues in the body. CD62L (L-selectin) functions as a “homing receptor” with adhesion properties for T cells and other lymphocytes enabling their passage through the high endothelial venules, by binding to CD34, to the secondary lymphoid tissues. These events in combination with integrins (i.e. LFA-1 family) and chemokine receptors (i.e. CCR7)

Question 27

what is Leukocyte adhesion deficiency (LAD)?

Answer 27

a congenital autosomal recessive immunodeficiency involving a defect in LFA-1 synthesis and or expression on the cell surface
and thus expression in select leukocytes. This results in an inability of the leukocytes to migrate to affected tissues

Question 28

explain how the γδ T cells distribute in domestic species

Answer 28

When the γδ TCR is expressed on the cell surface it is associated with CD3 and the zeta molecules. These T cells typically don’t express co-receptors CD4 or CD8 with exception in the intestine where a subset has been identified as CD8+. Similar to the a,b TCR, the γδ TCR is composed of 2 chains each containing a globular variable chain and globular constant chain in which the variable regions have the capacity to undergo some rearrangement. Since the genes that code for the γδ variable regions are fewer, the potential number of combinations for the γδ TCR binding sites are more limited.

Question 29

how are γδ T cells recognized and activated and what happens as a result?

Answer 29

phospholipid antigens, tend to have a more rapid response rate to select pathogens such as, mycobacterium, cytomegalovirus and plasmodium falciparum

Question 30

what are T cell cytokine associated with γδ T cells activation?

Answer 30

IFN-γ and TNF

Question 31

what immune-mediated diseases has γδ T cells been linked to?

Answer 31

BD, Type I diabetes, rheumatoid arthritis, multiple sclerosis

Question 32

where do α and γ chains originate from?

Answer 32

and J segments similar to the Ig light chains.

Question 33

where are β and δ chains derived from?

Answer 33

V, D and J chains similar to the Ig heavy chains.

Question 34

what are the two functions of cortical epithelial cells and medullary epithelial cells?

Answer 34

1. secrete cytokines (i.e IL-7) to aid in maintaining cell survival and inducing proliferation
2. thymocyte selection

Question 35

what cells are dispersed into the medullary region of the thymus?

Answer 35

dendritic cells and macrophages

Question 36

what is the congenital disease of DiGeorge Syndrome?

Answer 36

thymic epithelial cells fail to develop and thus an absence in a thymus. Since T cell differentiation cannot take place, these individuals are severely immunocompromised

Question 36

what is the congenital disease of DiGeorge Syndrome?

Answer 36

thymic epithelial cells fail to develop and thus an absence in a thymus. Since T cell differentiation cannot take place, these individuals are severely immunocompromised

Question 37

T cell Differentiation in the Thymus

Answer 37

the common lymphoid precursor cell differentiates into a precursor pre -thymic cell that enters at the cortico medullary junction to start is migration through the cortex. At this point, there are no discernable classic T cell surface molecules on its surface and thus it classified as a DN thymocyte. The gene for the TCR undergo rearrangement and the rest
of the previously described steps to yield either a pre-T cell expressing only the β chain or
γδ thymocyte. If the γδ TCR is expressed on the thymocyte, it exits out of the thymus to
become γδ T cells. So, these cells are only transiently in the thymus. The thymocyte pre-T cell expressing the β chain remains in the thymus migrates through the cortex then to the medulla. During the migration the α chain is synthesized and co-expressed to form the complete TCR. In addition, both the CD4 and CD8 co-receptors are upregulated in their expression on the cell surface of the thymocyte (i.e. ab+, CD3+, CD4+, CD8+) with the thymocyte classified as a DP (double positive CD4 and CD8) thymocyte, for short.
In fact, the majority of thymocytes in the thymus in a pre-pubic host are DP thymocytes.
The DP thymocytes migrate through the cortex into the medulla during which these cells
undergo a series of tests to determine if each will be a functional T cell and that it won’t overly react to self-MHC a process known as thymic selection. If it passes thymic selection, the thymocyte exits the thymus as a single positive (SP), CD4+ T cell or CD8+ T cell.

Question 38

positive selection

Answer 38

During migration through the cortex, the DP thymocyte encounters thymic epithelial cells that
present linear peptide self-antigens via MHC Class I and MHC Class II molecules. The primary
test by the epithelial cells is to determine whether the DP thymocyte has a functional TCR and
which MHC molecule it will recognize as self. This step is called positive selection. This is the
stage of selection in which the thymocyte commits to recognizing linear Ag through only one
MHC molecule directed in part by the co-receptor CD4 or CD8. The term self-MHC restriction of
T cell responses commemorates this relationship. Note, not all thymocytes recognize the
peptides and/or can bind to MHC. These cells are induced to undergo apoptosis.
If the DP thymocyte passes this test, it down regulates one of its 2 co-receptors and migrates to
the cortico-medullary junction where it encounters either a thymic dendritic cell or medullary
epithelial cell for its final test

Question 39

negative selection

Answer 39

, the thymocytes entering the cortico-medullary junction
have already committed to being either being CD4 or CD8. They encounter either a thymic
dendritic cell or medullary epithelial cell which present on their surface both MHC class I and
MHC class II molecules expressing linear peptides. The purpose of this selection is to ascertain
whether affinity of the thymocyte for its specific self-MHC is intermediate and is called negative
selection. If the binding affinity is too high, this could infer that the thymocyte has an
autoreactivity to self-antigen. If this were to occur, the thymocyte would be induced to die via
apoptosis. T cell differentiation through the thymus is believed to take a few weeks. As one can
see, T cell differentiation is highly regulated.
If the thymocyte passes negative selection, it can stay in the thymus for a few days after which
guided by adhesion molecules and chemokine receptors it migrates out of the thymus to
circulate through the secondary lymphoid organs in search of its cognate linear peptide Ag.
Once a naïve T cell recognizes its cognate linear Ag peptide presented by MHC, it clonally
expands into effector T cells and memory cells. The effector T cells are activated to combat the
antigen response and will continue until the antigen response abates then will likely be induced
to die via apoptosis. Memory cells are already primed to the antigen and remain in sort of a
“cell cold storage” until activated

Question 40

Natural Killer T (NKT) cells

Answer 40

subset of T cells that express a TCR and cell surface
protein NK1.1. NKT cells recognized glycolipids complexed through CD1d and not MHC. The TCR
of the NKT cells is generated via one V gene and a limited number of V genes it usage is
referred to as semi-variant and thus believed to respond to a limited number of antigens. The
current belief is that these cells display both innate and adaptive function

Question 41

T regulatory (Treg) cells

Answer 41

subset of CD4+ T cells (10% of the population)
denoted by cell surface protein CD25 and transcription factor Foxp3. They have a major role in
peripheral tolerance

Question 42

NK cells

Answer 42

lymphocytes that fall under the innate immunity umbrella. Most of these cells
originate from the bone marrow. Based on the literature a small subset can differentiate in the
thymus (duration unknown) as DN cells. Regardless, they emigrate out before TCR gene
rearrangement occurs. NK cells express cell surface molecules CD16 and CD56.

Question 42

NK cells

Answer 42

lymphocytes that fall under the innate immunity umbrella. Most of these cells
originate from the bone marrow. Based on the literature a small subset can differentiate in the
thymus (duration unknown) as DN cells. Regardless, they emigrate out before TCR gene
rearrangement occurs. NK cells express cell surface molecules CD16 and CD56.