Cytotoxic T cells

Question 1

Describe the major effect functions of cytotoxic T lymphocytes (CTLs)/ how they combat infection

Answer 1

When activated, naïve CD8+ T cells differentiate into CTLs. Activated CTLs:
o Migrate out of lymph nodes and into infected tissue
===Through same mechanisms as neutrophils
o Recognize viral peptides displayed on MHC class I molecules on infected cells
o Release (exocytosis) of granzymes and perforin to kill the infected cell in response to TCR binding of MHC class I molecule displayed by infected cell
o Release cytokines to promote inflammation in the infected tissue
o Makes interferon gamma (pro-inflammatory cytokine)

Question 2

How does perforin work?

Answer 2

Perforin- disturbs membrane integrity and it will insert itself into membrane of infected cell and polymerize
o This will allow entry of the granzyme into the cytosol

Question 3

How do granzymes work?

Answer 3

Granzymes are proteolytic enzymes which activate caspases that ultimately lead to activation of enzymes that degrade DNA called DNAses which leads to apoptosis

Question 4

What do the naive CD8+ T cell responses to viral infection involve?

Answer 4

o Cross-presentation of viral antigen by DCs
 Process of taking a virus from outside of dendritic cell and ending up with a peptide on class I MHC is called cross presentation
 A DC internalizes viral particles and fragments by endocytosis. Viral proteins are broken into peptides in proteasomes and displayed to CD8+T cells on MHC class I molecules
o Clonal selection and expansion of antigen-specific T cells
 Expansion of around x100,000
o Differentiation into effector cells called cytotoxic T lymphocytes (CTLs) which have cytotoxic granules that contain perforin and granzymes

Question 5

What antigen do CD8+ T cells recognize?

Answer 5

• CD8+ T cells recognize peptides bound to class I MHC protein

Question 6

What is required for naive CD8+ T cell activation

Answer 6

• In addition to presentation of antigen peptide on class I MHC protein, presentation of costimulatory molecules on the dendritic cells is also required
  o TCR recognises the peptide MHC, and CD28 recognizes costimulatory molecule B7 (dendritic cell specific)

Question 7

What does contraction mean?

Answer 7

o Contraction- the reduction of lymphocyte numbers

Question 8

Why does contraction occur in the immune response?

Answer 8

o Antigen-specific CTLs, B cells and helper T cells undergo massive expansion in response to infection
o After an infection is cleared, these lymphocytes are no longer necessary
o Effector T and B cells have functions that promote inflammation and tissue damage, which could make them dangerous
o After immune clearance of a microbe, the vast majority of lymphocytes that expanded to clear the microbe therefore undergo apoptosis
 This is because antigen receptor signaling is a survival requirement for many effector lymphocytes; the disappearance of antigen due to successful immune clearance is therefore equivalent to a loss of the lymphocyte’s survival signals

Question 9

What is the role of memory cells in secondary immune responses and how do they occur?

Answer 9

o A small number of antigen-specific lymphocytes differentiate into memory cells
o Memory cells can persist for many years and are the mediators of immunologic memory
o After the adaptive immune system has mounted an effective response and cleared a particular microbe, memory T and B cells can be reactivated by a subsequent exposure to the same type of microbe
o There may be some delay in a memory response as memory cells proliferate and gain effector functions, but a memory response is generally faster and more robust than a primary response

Question 10

What is the primary immune response?

Answer 10

o The first adaptive immune response to a particular type of pathogen is known as the primary immune response

Question 11

What is the secondary immune response?

Answer 11

o A subsequence response to the same type of pathogen re-activates memory cells and is known as a secondary immune response

Question 12

Why do therapeutic checkpoint blockade cancer therapies target CTL function?

Answer 12

o CD8+T cells have a hard time killing tumours as they are not active enough

Question 13

What is checkpoint blockade cancer therapy?

Answer 13

Checkpoint blockade is a new type of therapy that involves using monoclonal antibodies that bind to and block inhibitory receptors on the T cells

Question 14

What are the key inhibitory receptors targeted by checkpoint blockade cancer therapies? Where is each located?

Answer 14

o Key inhibitory receptors targeted by these monoclonal antibodies are CTLA-4 and PD-1
o CTLA-4 blockade occurs in lymph nodes; PD-1 blockade occurs in tissue

Question 15

How does CTLA-4 checkpoint blockade therapy work?

Answer 15

o This prevents dendritic cells accidentally engaging CTLA-4 instead of the costimulatory molecule CD28
 CTLA-4 binds to B7 with high affinity. This prevents binding of CD28 to B7, thus preventing costimulatory signaling
o Blocking of CTLA-4 by antibody forces proliferation and expansion of T cells which provides more cells to kill the tumour

Question 16

How does PDL1 checkpoint blockade therapy work for cancer?

Answer 16

o PDL1 is expressed on tumours so that they can exhaust the T cells and evade the immune system
 If you block PD-1 with antibody, the tumours can’t exhaust the T cells/ it will revive the T cells

Question 17

What are the physical symptoms of hepatitis C liver disease?

Answer 17

o Physical symptoms of liver disease:
o Punctate vessels
o Jaundice in the eyes
o Rashes
o Swelling of breast tissue
o Redness of the palms
o Swelling of ankles

Question 18

How is the liver checked in hepatitis C coindication?

Answer 18

o Checking the liver
o Liver is under the right side of the abdomen in the rib cage
o Sethoscope
o Percuss looking for changes in dullness
o Palpate: make patient take deep breath in and out so see if you can feel the liver size
 Because the liver is covered by the rib cage, a normal liver can’t be felt by palpitation -> in a patient with liver enlargement due to active hepatitis, he would be able to feel the liver by palpation
o Enlargement of liver and tenderness represents liver inflammation and injury

Question 19

How does hepatitis C work?

Answer 19

o Hepatitis viruses are not cytopathic: hepatitis viruses instead destroy the liver by inviting a cytotoxic T lymphocyte response which should eradicate virus infected cells but can actually injure the liver and cause inflammation
o Hepatitis C evades immune containment leading to another burst of viral reproduction that leads to another cycle of liver injury that invites another attempt by the host immune response to contain it
 This leads to liver tests going up and down in a sawtooth pattern

Question 20

What is the role of CTLs in hepC virus?

Answer 20

o CTLs Mediate Viral Clearance and Liver Injury in the Acute Phase of HCV
o It may seem paradoxical that CTLs can contribute to liver injury but also mediate immune clearance of HCV. Several studies have shown that an effective CTL response is critical for clearing HCV in the acute phase of infection. Moreover, the expansion of virus-specific CTLs during acute infection is tightly correlated with markers of liver damage, suggesting that CTLs are killing HCV-infected hepatocytes.
o Patients who spontaneously clear HCV in the acute phase of infection are not likely to suffer lasting liver damage, because the liver has a remarkable capacity for regeneration.

Question 21

What happens during the chronic phase of infection in hepatitis C virus?

Answer 21

o A Murkier Picture in the Chronic Phase of Infection
o In contrast, immune-mediated damage in chronic infection can have lasting consequences, including cirrhosis and liver cancer.
o The cause of immune damage in the chronic phase of infection is not entirely understood, but CTLs may be involved
o Innate immune cells called natural killer (NK) cells probably also contribute to inflammation and hepatocyte damage. NK cells are cytotoxic cells that express many of the same lethal molecules as CTLs, but they do not have T cell receptors.

Question 22

What are the two major classes of adaptive immune lymphocytes?

Answer 22

-T cells
-B cells

Question 23

What type of immunity do B cells coordinate?

Answer 23

Humoral adaptive immunity

Question 24

What type of immunity do T cells coordinate?

Answer 24

cell-mediated adaptive immunity

Question 25

What effector cell does CD8+ T cells become?

Answer 25

Cytotoxic T cells

Question 26

What effector cell does CD4+ T cells become?

Answer 26

Helper T cells

Question 27

What effector cell does B cells become?

Answer 27

Plasma cells

Question 28

What happens after an infection is cleared?

Answer 28

o Effector lymphocytes can migrate into inflamed tissue to function in microbial clearance
o Aften an infection is cleared by innate and adaptive cells, lymphocytes undergo apoptosis and homeostasis is restored
o Some memory cells persist: if the same microbes invade the tissue, the memory cells rapidly respond

Question 29

How do T cells generally function?

Answer 29

o T cell functions include direct killing of infected cells, activation of innate immune cells and activation of B cells