Lecture 9 - Cell Mediated Immune Responses

Question 1

Intracellular microbes

Answer 1

They replicate within the cytoplasm of host cells, where they are protected from microbicidal activities

Many viruses enter host cells through cell surface receptors

CD8+ T lymphocytes destroy cells infected with microbes. CD4+ T lymphocytes also help B cells produce antibodies

Question 2

Costimulatory Signal 1

Answer 2

TCR complex has a division of labor for TCR signalling. Allows for detection of an array of ligands that can cause a series of T cell responses:

1. TCR variable region detects antigenic peptide.
2. The presenting MHC molecule directs the T cell response (cytotoxic versus T helper).
3. Conserved CD3 and ζ complexes signal to the T cell

Question 3

Integrins

Answer 3

Stabilize the T cell to APC interaction

Eg. LFA-1

Question 4

LFA-1 adhesion

Answer 4

Major T cell integrin that binds ICAM-1 on APCs

1. LFA-1 is present in a low-affinity binding state on resting naïve T cells.
2. Exposure to chemokines converts LFA-1 to a high affinity state that clusters within minutes.
3. T cells bind APCs strongly in the cell interface of TCR-peptide-MHC contact.
4. Activation of the TCR complex is strengthened.
5. TCR signaling further strengthens the affinity of LFA-1 for ICAM-1, thereby increasing the strength of T cell - APC interactions and further stabilizing T cell signaling.

Question 5

Costimulatory Signal 2

Answer 5

After infection, APCs present microbial peptide antigens on MHC molecules

At the same time, microbial PAMPs stimulate expression of costimulators on APCs. T cells that respond to MHC-microbial antigen complexes also receive a second signal (i.e. B7) from the APC

Results in a fully active T cell that contributes to the anti-microbial immune response

Question 6

Costimulatory signals

Answer 6

Stimulatory signals from APCs that activate T cells

— Signal 1 = antigen-specific TCR engagement of MHC + peptide
— Signal 2 = contact with costimulatory ligands
— Signal 3 = cytokines directing T-cell differentiation into distinct effector cell types

Question 7

Signal 3

Answer 7

Cytokines directing T-cell differentiation into distinct effector cell types

Question 8

Differentiation

Answer 8

The process by which a cell becomes distinct or specialized, acquiring functionality lacking in naïve cells

Differentiation coincides with clonal expansion and leads to the generation of large numbers of differentiated effector cells

Question 9

T Cell Differentiation

Answer 9

TCR signalling changes gene expression and causes differentiation of naive T cells into effector cells, cytotoxic CD8+ T cells, or helper CD4+ T cells. After binding, B cells and macrophages become activated. Dendritic cells increase secretion of costimulators, furthering CD4+ T cell activation

CD4+ T cells differentiate into subsets: Type 1 and Type 2 (by proteins TH1 and TH2)
— Type 1 (TH1) produces interferon–γ (IFN-γ)

Question 10

CD40L

Answer 10

Surface molecule expressed by active CD4+ T cells

CD40L binds CD40, on macrophages, B cells and dendritic cells.

Upon binding of CD40L to CD40, B cells and macrophages become activated

Question 11

Interferon-γ (IFN-γ)

Answer 11

A cytokine produced by Type 1 CD4+ T cells

— A potent activator of macrophages, thereby enhancing microbial killing.
— Also, it stimulates B cells to produce antibody isotypes that promote the phagocytosis of microbes.

Question 12

CD8 +T cell differentiation

Answer 12

Initially, proliferation of the activated cell to deal with the infection

As the infection is cleared, they die off or differentiates into a smaller population of CD8+ memory cells.

Question 13

Perforin

Answer 13

Secreted by CD4+ T cells to a target cell that produces pores on the target allowing apoptotic inducers inside

Question 14

T Cell Activation

Answer 14

1. Activated T cells produce cytokines.
2. Cytokines drive clonal expansion of stimulated T cells.
3. Some activated T cells differentiate from naïve to effector cells, destroying microbe infected cells.
4. Others become memory T cells - functionally inactive, but very long-lived (months to years) and respond rapidly to the same microbe.
5. Microbial destruction removes antigen, resulting in a decline of the population of the responding clone.

Question 15

Cytokines

Answer 15

Produced by T cells in response to antigens and costimulators and by macrophages

Can be paracrine or autocrine to stimulate multiple arms of the immune response

1. In the absence of antigen the number of antigen-specific T cells is very low.
2. APCs present antigens to T cells.
3. Cytokines and stimulation by APCs leads to a rapid increase in T cell numbers.
4. T cells diminish microbial numbers.
5. Declining microbial numbers = less Ag, costimulators and cytokines. As a consequence, T cell numbers drop.

Question 16

DEVELOPMENT OF MEMORY T CELLS

Answer 16

A fraction of antigen-activated T lymphocytes that persist as memory T cells after an infection has passed

They reside in lymphoid tissues, in mucosal barriers and in circulation

They do not continue to produce cytokines or kill infected cells, but they may do so rapidly upon re-infection

Question 17

Lack of costimulator signals from APCs

Answer 17

Without microbial antigens, any peptide presented on an MHC molecule is a self-peptide. A TCR that recognizes it is auto-reactive.

The naïve T cell does not receive a second signal (costimulator) and becomes anergic-critical protection against auto-reactive lymphocytes in periphery.

Question 18

A productive T cell response

Answer 18

Barrier: T cells must encounter antigen.
Solution: APCs concentrate antigens in the lymphoid organs.

Barrier: T cells must determine the appropriate response (CD4+ or CD8+).
Solution: Class I and Class II MHC molecules direct the specificity of the response.

Barrier: 3. T cells must encounter antigen long enough for T cell signaling to occur.
Solution: Adhesion molecules tighten interactions between T cells and APCs.

Barrier: 4.The T cell response must be directed against microbial antigens and not harmless proteins.
Solution: 2nd signals ensures responses are elicited against microbial antigens.

Barrier: 5. A small number of T cells have to mediate the initial response.
Solution: Amplification mechanisms (clonal expansion, cytokine production, etc.) boost the T cell response.