T-cell Mediated Immunity

Question 0

What are the 2 ways by which DCs present antigens to T-cells?

Answer 0

1) Receptor mediated endocytosis of extracellular bacteria, antigenic proteins or virus particles - present antigen via MHC class II molecules to CD4+ T-cells
2) antigen peptides processed by proteasome and present on DC surface via MHC class I molecules to CD8+ T-cells

Question 1

Why are macrophages not as effective as an APC to naive T cells as dendritic cells?

Answer 1

Macrophages are sessile cells that reside in peripheral tissues. Naive T cells are found in circulation or in LN. Macrophages in the LN can activate naive T cells if they phagocytose antigens that have been carried to the LN via lymph or blood or ECF. DCs are migratory cells that carry load of antigen to the nearest LN.

Question 2

What is the significance of CCR7 on dendritic cells?

Answer 2

Activated DCs express CCR7 on the cell surface which binds with chemokine CCL21 resulting in pathogen laden DC to enter LN and concentrate on presenting antigen to naive T-cells.

Question 3

What are the homing mechanisms used to draw naive T cells to secondary lymphoid tissue?

Answer 3

1) Chemokines CCL21 & CCL19 (released by stromal cells & DCs in the LN cortex and are on the surface of HEVs) bind to CCR7 receptor on naive T cells
2) Adhesion molecules - upon initial contact with HEV, L-selectin on T-cell interacts with CD34 and Gly-CAM-1 on HEV surface causing naive T-cell to slow down and attach to the surface of the HEV. Eventually the T-cell squeezes between endothelial cells to enter the LN cortex.

Question 4

What are the types of adhesion molecules involved in a naive T-cell entering the LN cortex?

Answer 4

1) L-selectin on the naive T-cell surface binds to CD34 and Gly-CAM-1 on endothelial cells of HEV (initiates cell rolling)
2) T-cell integrin LFA-1 binds to ICAM-1 and ICAM-2 on endothelial cell surface to strengthen attachment (tightly binds naive T-cell w/subsequent diapedesis into LN

Question 5

What is the mechanism involved in naive T-cell binding to DC?

Answer 5

Initial contact involves CD2 on naive T-cell binding to LFA-3 on APC. This contact is strengthened by LFA-1 on T-cell binding to ICAM-1 & ICAM-2 on APC. An additional interaction involves another adhesion moleculue, DC-SIGN on APC binding to ICAM-3 on T-cell.

Question 6

What 3 signals must occur at the same time between an APC and naive T-cell in order for the T-cell to become fully activated (proliferate and differentiate)?

Answer 6

1) peptide:MHC complex engages co-receptors CD4 or CD8
2) Co-stimulatory signaling between B7 ligands on the same APC with CD28 receptors on T-cell surface
3) cytokines released by APC direct T-cells to differentiate along a specific pathway to become an effector T-cell

Question 7

Which cells express MHC class II molecules?

Answer 7

DCs, macrophages, thymic epithelial cells and activated B-cells

Question 8

What are CTLA-4 receptors?

Answer 8

These are receptors on activated T-cells that bind to B7 molecules on DCs 20X more than CD28 receptors. This binding dampens T cell activation and proliferation.

Question 9

What are the steps in MHC class I processing of antigens?

Answer 9

1) pathogenic proteins degraded into peptides by cytoplasmic proteasome
2) transporters TAP-1 & TAP2 translocate peptides into ER lumen where some peptides fit into the groove of MHC class I molecules
3) MHC class I molecule folds stably and is exported to the cell surface where CD8+ T-cells recognize the MHC plus foreign peptide and destroys infected cell

Question 10

What are the steps in MHC class II processing of antigens?

Answer 10

1) APC performs phagocytosis of free virus, antigens
2) Phagosome fuses with lysosome => phagolysosome, which degrades pathogen into peptides
3) Phagolysosome fuses with MHC class II molecule budding off from ER
4) Peptides displace invariant chain and fit into groove of MHC class II molecule as vesicle moves to cell surface
5) CD4+ T-cells scan MHC molecule w/foreign peptide and release cytokines that recruit CD8+ T-cells and B-cells

Question 11

What is Chediak-Higashi syndrome?

Answer 11

DCs are unable to process antigen and present it to T-cells due to a defect in vesicular fusion.

Question 12

What TLRs on DCs are triggered by virus, intracellular bacteria or parasite, which cytokines are released by the DC, and which kind of T-cell response is activated?

Answer 12

TLRs 3,7-9. Cytokines released are IFN-I and IL-12 => activate CD4 Th1 cells that release IFN-gamma (macrophage activation), TNF-a and IL-2 (lymphocyte proliferation), lytic granules (Granzymes and perforin)

Question 13

Which TLRs on DCs are triggered by extracellular bacteria, what cytokines are released by DCs and what kind of T-cell response is activated?

Answer 13

TLRs 2,4,5. DC releases cytokines IL-10 and IL-4 => activates CD4
Th2 cells which release IL-4, IL-5 (help B cells become plasma cells), IL-6 (acute phase proteins), IL-10 (anti-parasitic eosinophil response)

Question 14

What TLRs on DCs are triggered by gut bacteria and parasites, what cytokines are released by DCs and what kind of T-cell response is activated?

Answer 14

TLRs 1,2,6. Cytokines released are IL-23, TGFB and IL-6 => activates CD4 Th17 cells (proinflammatory) that release IL-17 (chiefly), IL-12, IL-22, IL-6 (activates and recruits PMNs, other inflammatory cells); implicated in autoimmunity inflammatory disease

Question 15

How do naive T-cells differentiate into T-reg cells?

Answer 15

DCs release cytokines IL-6 and TGF-B => activates T-reg cells that secrete TGF-B, IL-10, CTLA-4 (down-regulate immune response and prevent autoimmunity)

Question 16

What happens if T-cells do not receive signals for activation?

Answer 16

No 1st signal - no activation
No 2nd signal - anergy/tolerance
No 3rd signal - incomplete expansion/differentiation

Question 17

What are CD8+ T-cell effector fxns?

Answer 17

Primed CD8 cells migrate to site of infection, recognize peptide antigens on any cell that expresses MHC class I molecules, kill the recognized cell without co-stimulation.

Question 18

What are the 2 mechanisms by which CD8+ T-cells destroy infected cells?

Answer 18

1) Pore formation: Perforin granules form pores in target cell membrane causing leakage of intracellular content or granzyme-serine proteases are injected thru pore and induce apoptosis
2) Fas ligand on CTL binds to Fas receptor (CD95) on target cells and induces DNA fragmentation

Question 19

What is hemophagocytic lymphohistiocytosis?

Answer 19

Deficit in perforin does not allow CTLs and NK cells to kill infected cells. Cells are cont. stimulated to proliferate and accumulate causing hepatosplenomegaly, bone marrow infiltration and anemia, coagulopathy. Rare familial disease.

Question 20

What is X-linked lymphoproliferative syndrome?

Answer 20

Inappropriate activity of SAP(signaling molecule involved in activating/inhibiting CTLs). NK cells are depressed, CTL activity is enhanced resulting in recurrent otitis media, high levels of atypical lymphocytes in CBC and acute EBV infection at presentation

Question 21

What is the transcription factor expressed by naive T-cells that commit to becoming a T-reg cell?

Answer 21

FoxP3

Question 22

What is Bare Lymphocyte syndrome?

Answer 22

An immunodeficient condition marked by repeated infections due to a defect in the expression or export of MHC molecules so that there is no “immunological synapse” between the DC and T-cell (T-cell activation doesn’t take place)

Question 23

What is Wiscott-Aldrich Syndrome?

Answer 23

T-cell signaling is disrupted after the initial activation of T-cell due to a problem with T cell cytoskeleton. No T-cell differentiation takes place leading to multiple sensitivity to infection, eczema, asthma, bloody diarrhea, hemolytic anemia. (Al tissues have a problem with the cytoskeleton)

Question 24

How is intracellular signaling propagated from TCR/CD3 to the nucleus of the T-cell?

Answer 24

Cytoplasmic tails of CD3 contain immunoreceptor tyrosine-based activation motifs (ITAMs) that associate with tyrosine kinases in the cytoplasm => induces intracellular signaling that lead to activation of NF-kB transcription factor => gene expression for cell proliferation and differentiation

Question 25

What role does IL-2 play?

Answer 25

IL-2 is a cytokine released by T-cells. Binds to IL-2 receptors on T cells to drive clonal expansion of the activated cell

Question 26

What drugs are IL-2 antagonists?

Answer 26

Cyclosporin, Tacrolimus, Rapamycin