Cell-Mediated Immunity

Front 1

Describe the functions of RAG-1 and RAG-2:

Back 1

-Enzymes that mediate the joining and cleaving of gene segments during V-DJ recombination.

-People deficient or have mutations in RAG-1 or 2 will not be able to make T or B cells--> severe combined immunodeficiency.

Front 2

Purpose of CMI?

Back 2

-Deal with intracellular pathogens--viruses, some bacteria, some parasites.

Front 3

Where does antigen recognition occur?
What steps have to occur right after it occurs?

Back 3

-2˚ lymphoid tissues.
-T cell proliferation and differentiation. This also occurs in 2˚ lymphoid tissues.
-They then enter the blood, respond to cytokine/chemokine signals, and then elicit their functions--CD8s kill, CD4s make cytokines.

Front 4

BIG PICTURE STEPS IN THE ACTIVATION (PRIMING) OF T CELLS:
-Going from mature but naive to effector cells.

Back 4

-Cytokines are produced (*IL-2 is most important)
-Enables clonal expansion (proliferation)
-Other signals lead to differentiation.

Front 5

WHAT 3 SIGNALS ARE REQUIRED TO PRIME T CELLS?

Back 5

-TCR Signaling (SIGNAL 1)
-Costimulatory interaction (SIGNAL 2)
-Cytokine signaling (especially IL-2, THIS IS SIGNAL 3)

Front 6

Most important APC in initial stages of infection?

Back 6

-Dendritic cells.

-Have high levels of class I and class II MHC molecules.

-Have high levels of B7 proteins for costimulation.

-They are "loaded" with MHCs and with B7s by the time they get to a lymph node.

Front 7

What is an immunological synapse?

Back 7

-SIGNAL 1!
-Occurs when a TCR encounters its cognate antigen on an APC's MHC protein.
-It's defined as the point of contact between an APC and TCR.
-When this occurs, the T cell begins to upregulate adhesion molecules, which stabilize the contact b/t APC and TCR.

-Engagement of TCR receptor signals for T cells to proliferate.

Front 8

Describe the importance of interaction b/t costimulatory molecules:

Back 8

-SIGNAL 2!
-Interaction b/t CD28 on T cell and B7 on the APC.
-Necessary for T cell activation and IL-2 production!
-W/o costimulation, the T cell is in a state of "anergy," meaning it's inactive.

Front 9

What's SIGNAL 3 for T cell Activation/Priming?

Back 9

-INTERACTION WITH CYTOKINES
-Upregulation of cytokine receptors (IL-2R) and response to cytokines (IL-2) = Signal 3
-Signals nucleus to lead to differentiation of the T cell--CD4, CD8, or memory cell.

Front 10

What is Cross-Presentation of antigens and why is it important?

Back 10

-CD8 cells aren't great at making cytokines.
-APCs will present antigen to both a CD4 and a CD8 cell using their MHC II and I proteins.
-The CD4 cell makes IL-2, which stimulates the CD8 cell to proliferate.

*If there is a low number of CD4 cells (HIV), you will get lower CD8 activity.

Front 11

End results of T cell differentiation: 4

Back 11

-When T cells leave the thymus, they leave as antigen-naïve CD4+ or CD8+ cells.

-CD8+ cells that encounter their “cognate antigen” in the peripheral lymphoid system, become activated to become *Cytotoxic Lymphocytes (CTLs).

-CD4+ cells that encounter their “cognate antigen” in the peripheral lymphoid system, become activated to become Helper T cells (*Th1,*Th2, *Th17 cells).

Front 12

Describe CD4 cells. 3

Back 12

-The “quarterback” of the immune system.
-Directs action by secreting cytokines that have dramatic effects on other immune cells.
-Helper T cells are “cytokine factories”
-Express CD40 ligand, which binds CD40 on an APC.

Front 13

What differentiates the 3 kinds of CD4 cells?

Back 13

-Depends on what they secrete! Know what they secrete!
-The cytokines they secrete determine their function.

Front 14

What signals determine which of the 3 Th subtypes a T cell will turn into?

Back 14

-Regulated by the stimuli that naïve CD4+ T cells receive when they encounter microbial antigens. Know these!
-They are made by macrophages, etc.

Front 15

Th1 cells:
what are they effective against?
what cytokines are at play? what do the cytokines do?

Back 15

-Effective against intracellular bacteria and viruses.
-IL-12 promotes Th1's cytokine production (esp. IFN-g)
-Th1 cytokines activate phagocytic killing and production of antibodies that promote the ingestion of microbes by the phagocytes (opsonization).

Front 16

Th1 Cell Differentiation and Function:

Back 16

-Importance of IFN-g.
-Activates macrophages
-Leads to B cell antibody production/secretion --> opsonization of invader by macrophages.

Front 17

Describe Th2 cells:

Back 17

-Effective against extracellular pathogens (parasites like worms for example)

-Th2 cytokines activate humoral immune responses by stimulating production of IgE and other antibodies isotypes that function in neutralization.

-Also promote eosinophil-mediated immunity (good at fighting worms like helminths).

Front 18

Role of IL-4 in determining differentiation of Th cells:

Back 18

-IL-4 engages Th cells to make the cell become a Th2 cell.

Front 19

Steps involved in Th2 cell differentiation and function:

Back 19

1) TCR engagement: Antigen presentation -> T cell proliferation/differentiation
2) Costimulation
3) Cytokine signaling (IL-4) -> Th2

-Th2 can now produce more IL-4, which causes B cells to produce IgG and/or IgE.

Front 20

Th2 cells produce several ILs. What are they and what do they do?

Back 20

IL-4: causes B cells to produce IgG and/or IgE; also activates macrophages?
IL-5: Activates eosinophils, which fight parasites.
IL-13: Activates macrophages?

Front 21

What's the role of Th17 cells?
What molecules do Th17 cells secrete?
What cytokines cause a Th cell to become a Th17 cell?

Back 21

-To fight fungal and extracellular pathogens and chronic inflammatory disorders (active in MS, systemic lupus)

-Th17 cells produce chemokines--IL-17 and IL-22


-TGFß and IL-6 (proinflammatory cytokines) increase Th17 differentiation.

Front 22

DESCRIBE THE PROCESS OF MIGRATION OF EFFECTOR T CELLS TO ANTIGEN SITES:

Back 22

-It's an antigen independent process (T cell has already been activated).
 
-Activated cells use receptors to bind to ligands induced on endothelium by cytokines produced during infection.
 
-T cells that recognize antigens are retained in extravascular tissues by ADHESION to extracellular matrix

Front 23

What are the EFFECTOR FUNCTIONS OF CD4+ HELPER T CELLS?

Back 23

-Specificity of cell-mediated immunity by CD4+ cells is a function of the T cell, but elimination of the pathogen is a function of the ACTIVATED cells, e.g. macrophages, eosinophils.
*CD4 cells have no cytotoxic or phagocytic activity, and cannot directly kill infected cells or clear pathogens.
*They function as “quarterbacks”; their role is to manage the immune response by directing other cells to perform these tasks.

Front 24

What accounts for the specificity of the Th1 response or the ability of Th1 cells to activate macrophages?

What are the effector functions of Th1 and Th2?

Back 24

-Antigen recognition!

-For Th1 cells, elimination of the pathogen is a function of the activated macrophages that have phagocytosed pathogens.

-For Th2 cells, elimination of the pathogen is a function of the activated eosinophils.

Front 25

Give two examples of how the innate and adaptive immune system interact with each other, using specific cytokine examples:

Back 25

-An infected APC makes IL-12, which causes a CD4 cell to become a Th1 cell, which makes IFN-g, which activates more macrophages to kill microbes.

Front 26

What determines the balance between Th1 and Th2 cell activation?

Why is that balance important?

Back 26

-The pathogen itself determines the balance.

-THE BALANCE BETWEEN Th1 AND Th2 CELL ACTIVATION IS AN IMPORTANT DETERMINANT OF THE OUTCOME OF THE INFECTION.

-If the differentiation or signaling steps get messed up, the infection won't clear as well as it should.

Front 27

EFFECTOR FUNCTIONS OF CD8+ CYTOLYTIC T CELLS:
What mediators do they use to do their job?

Back 27

CD8+ cytolytic T cells (CTL) are selective and serial killers of infected cells!
-Use perforins and granzymes.

Front 28

What happens when T cell function becomes impaired?
List 3 genetic diseases and briefly describe them.

Back 28

-DiGeorge Syndrome: incomplete development of thymus (or absent thymus). -> reduced number of T cells; improperly activated T cells. B cell responses are impaired since CD4 cells are messed up. Also involves abnormal facies.

-Bare lymphocyte syndrome (BLS) type II: impaired expression of MHC class II molecules. Impaired CD4 and B cell function.

-TAP deficiency (BLS I): impaired expression of MHC class I molecules. Prone to viral infections since peptide antigen isn't getting loaded onto ER via TAP.

Front 29

List six pathogens that have evolved ways to evade CMI. How do they do it?

Back 29

Front 30

A male infant developed tonic convulsions a few days after birth and was found to be hypocalcemic. Of note, he was born with a cleft palate, widely spaced eyes, and ears residing lower than normal. A lateral chest radiograph revealed a diminished thymic shadow and a diagnosis of DiGeorge syndrome is made. What is the pathogenesis of this condition?
 
A. Defective expression of costimulatory molecules.
B. Low to severely decreased T cell numbers in the blood.
C. Reduced antigen processing by dendritic cells.
D. Low to severely decreased B cell numbers in the blood.

Back 30

B. Low to severely decreased T cell numbers in the blood.

Front 31

A 2-month-old infant presents with severe pyoderma over much of her body. Her history is significant for other infections including pneumonia and for bruising very easily. Physical exam reveals an ill infant with large areas of hypopigmentation of the skin, silvery hair, and very pale eyes. Gingival inflammation and bleeding of the gums and generalized lymphoadenopathy are noted. A definitive diagnosis of Chediak-Higashi syndrome is made by examination of a blood smear that showed unusually large granules within neutrophils. What is the pathogenesis of this condition?
 
A. Defective expression of pattern recognition receptors.
B. Mutation of the phagocyte oxidase gene.
C. Defect in production of the cytokine interferon-gamma (IFN-g)
D. Inability of neutrophils to fuse lysosomes with the phagosome, resulting in defective microbicidal activity.

Back 31

D. Inability of neutrophils to fuse lysosomes with the phagosome, resulting in defective microbicidal activity.

Front 32

The term immunologic synapse refers to:
 
A. PAMP recognition by pattern recognition receptors.
B. restriction of CD4+ T cells to MHC class I.
C. selective unresponsiveness of T cells.
D. T cell recognition of soluble molecules.
E. the interface between antigen-presenting cells and T cells.

Back 32

E. the interface between antigen-presenting cells and T cells.

Front 33

Which of the following naïve cells load peptide fragments into MHC class II molecules?
 
A. CD4+ T cells
B. CD8+ T cells
C. neutrophils
D. dendritic cells
E. NK cells

Back 33

D. dendritic cells

Front 34

A 2-year-old child exposed to an antigen for the first time already possesses a T cell with receptors specific for that antigen. Which of the following best explains this finding?
 
A. antigen-independent TCR gene rearrangement
B. antigen stimulation of T cell cytokine production
C. maternally derived T cells to that antigen
D. memory T cells that recognize the antigen
E. antigen-dependent TCR gene rearrangement

Back 34

A. antigen-independent TCR gene rearrangement