L5: T-Cells / Cell-Mediated Immunity

Question 1

Describe ontogeny of T lymphocytes

Answer 1

• Prothymocytes from bone marrow migrate to thymus where they become thymocytes
• Thymocytes differentiate into mature T cells within the thymus
• Mature T cells travel from thymus to peripheral lymphoid organs
• Memory T cells reside in bloodstream until needed to elicit cell-mediated immune responses

Question 2

List various forms of T cells in the body. What are their functions?

Answer 2

1. ) T-helper cells (CD4+)
   a. ) TH1: participate in cell-mediated immunity (IgG)
   b. ) TH2: participate in humoral immunity (esp. via IgE)
   c. ) TH17: enhances inflammation
   d. ) Tfh: promote germinal center formation in lymphoid organs
2. ) Cytotoxic T cells (CD8+): lyse virus-infected cells
3. ) Regulatory T cells (aka Treg cells): downregulate immunity

Question 3

What confers MHC restriction to the T cell?

Answer 3

• CD4 and CD8

- No the TCR itself

Question 4

Structure of TCR

Answer 4

• Heterodimer of alpha and beta chains, each chain has constant and variable regions similar to antibodies
• Short cytoplasmic tails
• Only has single antigen binding site
• Never secreted

Question 5

Associated transmembrane protein with TCR. Purpose?

Answer 5

• TCR’s cytoplasmic tails are not long enough to act as signal transducers
• It requires CD3 to transduce signal, cytoplasmic tails of CD3 are phosphorylated

Question 6

In order for a T-cell response to occur, one of the signals required are from co-stimulatory molecules/interactions. What are these?

Answer 6

• CD28 (on T-cell) binds B7 (on APC)

- CD40L (L = ligand on T-cell) binds CD40 (on APC)

Question 7

What are the 3 signals needed in order for a T-cell to become activated?

Answer 7

1. ) Processed peptide expressed on class I or II MHC
2. ) Co-stimulatory molecules (CD28:B7, CD40L:CD40)
3. ) Production and liberation of cytokines that bind T cells

Question 8

What is hyperIgM syndrome?

Answer 8

• Immune deficiency where T-cells don’t express CD40L

Question 9

Describe characteristics and functions of CD4

Answer 9

• transmembrane glycoprotein consisting of a single polypeptide expressed on 2/3rds of T cells, most are TH cells, present in small quantities of macrophages
• function: CAM, signal transduction, restricts T cells to class II MHC

Question 10

Describe characteristics and functions of CD8

Answer 10

• homo/heterodimer expressed on a subset of T cells

- function: CAM, signal transduction, restricts T cells to class I MHC

Question 11

Discuss activation and signal transduction in T cells

Answer 11

1. ) TCR binds to MHC-bound antigen, co-stimulatory signals and cytokine stimulation
2. ) Phosphoinositide pathway, RAS, MAP kinase pathways are activated. PKC and other kinases phosphorylate transcription factors
3. ) AP-1 (TF) initiates IL-2 cytokine production (autocrine)
4. ) Mitosis causes expansion of antigen-specific clones to amplify an immune response 48-72 hours after stimulation through TCR

Question 12

What is required for naïve T cells to develop into TH1 cells?

Answer 12

• TH1 cells will develop when naïve T cells receives signaling from IL-12, which is produced under conditions of inflammation caused by various bacteria, viruses and other pathogens

Question 13

Action of TH1-mediated immunity on macrophages? On CTLs?

Answer 13

• TH1 cells cause classical macrophage activation through release of IFN-gamma, which enhances microbial killing
• TH1 cells produce cytokines that stimulate CTL differentiation. They also enhance the ability of APCs to stimulate CTL differentiation

Question 14

What is required for naïve T cells to develop into TH2 cells?

Answer 14

• TH2 cells develop when they receive signaling from IL-4, thought to be produced by mast cells or antigen-activated T cells

Question 15

Action of TH2-mediated immunity?

Answer 15

• TH2 cells produce IL-4, IL-13 and IL-5, which directs the immune response toward IgE production for anti-parasite defense particularly against helminth infestations
• Can also lead to alternate macrophage activation for tissue repair

Question 16

What is required for naïve T cells to develop into TH17 cells?

Answer 16

• Exposure to IL-1, IL-6 (produced by DCs during anti-microbial defense) and TGF-beta (from various cell types)

Question 17

Action of TH17-mediated immunity?

Answer 17

• Secrete IL-17 and IL-22, which promote inflammation: antimicrobial peptides, increased barrier function, neutrophil response

Question 18

Describe how TH1 and TH2 responses are regulated

Answer 18

• TH1 and TH2 cytokines have antagonistic responses
• IFN-gamma produced in TH1 response, inhibits TH2 responses
• IL-4 and IL-13 produced in TH2 response, inhibits TH1 response

Question 19

How are CTLs activated?

Answer 19

• By TH1 cells that produce cytokines that stimulate CTL differentiation. TH1 cells also enhance the ability of APCs to stimulate CTL differentiation.

Question 20

Function of CTLs?

Answer 20

• destroy intracellular microbes (viruses, some bacteria), tumor cells and transplanted tissues and organs

Question 21

Process of CTL killing? Mechanisms?

Answer 21

1. ) Process: target cell binding and recognition of class I MHC, CTL activation, delivery of lethal hit, disengagement from target cell, death of target cell
2. ) Mechanisms:
   a. ) Perforin/granzyme-mediated killing: perforin facilitates delivery of granzyme B to target cells cytoplasm, granzyme B activates caspase pathway, cell death occurs through mitochondrial pathway of apoptosis
   b. ) Fas/FasL-mediated killing: binding of CTL-expressing Fas ligand to target cell Fas protein, activation of caspases, apoptosis