6: Effector Mechanisms of T Cell-Mediated Immunity

What do CD4+ cells recognize?

Microbes contained in phagocytic vessels are primarily controlled by CD4+ T cell mediated response responses

What do CD8+ T cells recognize?

Microbes residing in the cytoplasm (infected cells)

What determines whether CD4+ and CD8+ T cells are primarily responsible for eliminating an intercellular infection?

The location of the microorganism within the infected cell.

• Microbes contained in phagocytic vessels are primarily controlled through CD4 + T cells

• microbes resulting in the cytoplasm can be controlled by CD8+ cytotoxic T cells

What is the primary function of TH1 cells during infections involving microbes inside phagocytic vessels?

TH1 cells secrete cytokines that activate macrophages, increasing their ability to kill microbes they have ingested.

How do TH17 cells contribute to cell mediated immunity?

TH 17 cells promote inflammation by stimulating the recruitment and activation of inflammatory leukocytes, which help eliminate microbes

What is the primary function of CT 8+ cytotoxic T lymphocytes during intracellular infection?

CD8 plus cytotoxic lymphocytes recognize infected whole cells and kill them, eliminating cellular environment in which cytoplasmic microbes survive and replicate

What is the difference between macrophage activation and cytotoxic T cell killing?

• Macrophage activation enhances the destruction of microbes inside phagocytic compartments while preserving the host cell

• Cytotoxic T cell killing destroys the infected host cell itself

Which T cells subsets primarily defend against microbes within phagocytic vesicles?

CD 4+ TH1 cells activate macrophages, while CD 4+ TH 17 cells promote inflammation and recruit leukocytes

What does adoptive transfer of immunity mean?

The transfer of protective immune function from an immune donor to a recipient through the administration of immune cells

What happens when the immune T cells were transferred to the recipient mouse infected with Listeria?

The number of viable Listeria bacteria in the spleen remained relatively low over the four day observation period, demonstrating protective immunity

What happened when non-immunity cells were transferred to the mouse recipient infected with Listeria?

The bacterial burden in the spleen increased significantly overtime

What experimental findings demonstrates that T lymphocytes can transfer specific immunity against intercellular bacteria?

Recipients given immune T cells controlled listeria growth, whereas recipients given nonimmune T cells experienced a substantial increase in bacteria numbers

How did the results of the immune serum experiment differ from the immune T cell experiment?

Immune serum did not provide substantial protection against the intercellular listeria infection in this experiment

• Why? The serum contained antibodies. However, once listeria is inside a cell, it never comes out. Therefore, the antibodies will not have access to the listeria.

What conclusion can be drawn from the adoptive transfer experiments using immunity cells and immune serum?

Protection against listeria in these experiments depends primarily on cellular immunity mediated by T lymphocytes rather than transferable serum factors

What is the defining cytokine produced by TH1 cells?

IFN- γ

What is the principle target cell of TH1 cells?

Macrophages

What is the major immune reaction of TH1 cells?

Macrophage activation

what types of pathogens are primarily controlled by TH1 cells?

(host defense)

Intracellular pathogens

What role do TH1 cells play in diseases?

Autoimmunity and chronic inflammation are associated with inappropriate TH1 responses

What are the defining cytokines produced by TH2 cells?

• IL – 4

• IL – 5

• IL – 13

What is the principal target cell of TH2 cells?

Eosinophils

What are the major immune reactions mediated by TH2 cells?

• Eosinophil and mast cell activation

• Alternative macrophage activation

Which pathogens are primarily controlled by TH2 responses?

(Host defense)

Helminths, which are parasitic worms

What role do TH2 cells play in diseases?

Allergic diseases are associated with inappropriate TH2 responses

What are the defining cytokines produced by TH 17 cells?

• IL – 17

• IL – 22

What are the principle target cells of TH 17 cells?

Neutrophils

What is the major immune reaction mediated by TH17 cells?

Neutrophil recruitment and activation to promote inflammation and microbial elimination

What pathogens are primarily controlled by TH17 mediated immunity?

(Host defense)

Extracellular bacteria and fungi

What role do TH17 cells play in diseases?

Autoimmunity and inflammation are associated with inappropriate TH 17 responses

Which helper T cell subset is most directly associated with macrophage activation?

TH1 cells

Which helper T cell subset is most directly associated with eosinophil activation and helminth defense

TH2 cells

Which helper T cell subset is most directly associated with neutrophil recruitment?

TH 17

Which helper T cell subset is most directly responsible for assisting B cells in antibody production?

T follicular help cells

What type of pathogen initiates the TH1 response?

Bacteria presented by antigen presenting cells

What happens to naïve T lymphocytes following activation in the TH1 pathway?

They differentiate into TH1 effector cells

what cytokine is secreted by differentiated TH1 cells to activate macrophages?

IFN-γ

What is classical macrophage activation?

Activation of macrophages into a state characterized by enhanced antimicrobial activity and increased killing of ingested microorganisms

What is the major functional outcome of TH1 mediated macrophage activation?

Enhanced microbial killing (M1)

What is the sequence of cellular events in the TH1 effector response?

1. Bacterial antigen presentation

2. Naïve T cell activation

3. TH1 differentiation

4. IFN- γ secretion

5. Classical macrophage activation (M1)

6. Enhanced microbial killing

What does IFN- γ do?

Activates macrophages to kill pathogens and helps coordinate the immune response against intracellular infections.

What two major signals from TH1 lymphocytes activate macrophages?

IFN- γ secretion and interaction between CD40 ligand (CD40L) on the TH1 cell and CD40 on the macrophage

What initiates CD40 – CD40L interaction and IFN- γ secretion?

Pathogen recognized by an antigen presenting cell

Which molecule on the TH1 cell binds CD40 on the macrophage?

CD40 ligand (CD40L)

What is the function of CD40 – CD40L interaction during macrophage activation?

It provides an activating signal that contributes to enhanced macrophage antimicrobial activity

Which receptor on macrophages respond to IFN-γ released by TH1 cells?

The IFN- γ receptor

• IFNGR

What is the principle effect of IFN-γ signaling on macrophages?

It promotes classical macrophage activation, and increases their ability to kill ingested microorganisms

Which reactive antimicrobial molecules are produced by activated macrophages?

Reactive oxygen species (ROS) and nitric oxide (NO)

What is the major antimicrobial outcome of ROS, nitric oxide, and increase lysosomal enzymes?

Killing of microbes within phagolysosomes

Which cytokines are secreted by activated macrophages?

TNF, IL – 1, and IL – 12

What roles do TNF, IL –1 , and chemokines play in cell mediated immunity

They promote leukocyte recruitment and inflammatory responses

What role does macrophage derived IL – 12 play in cell mediated immunity?

Promotes TH1 differentiation and IFN- γ production

What happens to MHC molecule expression following macrophage activation?

MHC expression increases, strengthening the macrophages ability to present antigens to T lymphocytes

What happens to B7 costimulatory molecule expression, following macrophage activation

B7 expression increases, strengthening costimulatory signaling to T lymphocytes

How to increased MHC and B7 expression affect T cell response responses?

They enhance T cell activation and amplify the immune response

What is the role of phagolysosomes in activated macrophages?

They are intracellular compartments where ingested microbes are exposed to antimicrobial substances and lysosomal enzymes

How does macrophage activation amplify cell mediated immunity?

Activated macrophages increase microbial killing, recruit additional leukocytes, stimulate TH1 different through IL – 12, and enhanced T cell activation through increased MHC and B7 expression

Examples of antigen presenting cells that can present to TH1 cells:

Dendritic cells and macrophages containing ingested microorganisms

Which cytokine is produced by antigen presenting cells to promote differentiation of naïve CD 4+ cells into TH1 cells?

IL – 12

What happens to a naïve CD4+ T cell in response to antigen presenting and IL – 12?

They differentiate into TH1 effector lymphocytes

Which cytokinin is secreted by differentiated TH1 cells to activate macrophages?

IFN- γ

What happens to macrophages after receiving IFN- γ signals from TH1 cells?

They become activated and increased their ability to kill ingested microorganisms

Describe the cytokine mediated interaction between macrophages and TH1 lymphocytes

• Antigen presenting cells release IL – 12 to promote TH1 differentiation

• TH1 cells release IFN-γ , which activates macrophages and enhances microbial killing.

Which antigen presenting cell produces IL – 12 during TH1 differentiation?

Dendritic cells

Which immune cell produces IFN- γ during the development of TH1 responses?

Natural killer (NK) cells

Which transcription factor is the master regulator of TH1 differentiation?

T – bet

Which STAT proteins are associated with TH1 differentiation?

STAT1 and STAT4

Which STAT protein is associated with IL – 12 in TH1 development?

STAT4

Which STAT protein is associated with IFN- γ signaling in TH1 development

STAT1

What is the relationship between T – bet and TH1 differentiation?

T -bet is a transcription factor that directs antigen activated T cells toward the T1 lineage

Which pathogens primarily initiate the TH2 immune response?

Helminths and protein antigens

What happens to naïve CD 4+ T Cells after antigen presentation during a TH2 response?

They proliferate and differentiate into TH2 effector cells

Which TH2 cytokine promotes B cell antibody production and class switching towards IgE?

IL- 4

Which antibody classes are identified as products of the TH2 associated antibody response?

IgE and IgG4

• IgG1 in mice

What is the function of IgE during TH2 mediated immune responses?

IgE participates in mast cell activation and degranulation during responses against parasitic worms and in allergic reactions

What is mast cell degranulation?

The release of preformed mediators from mast cell granules, following activation

Which cytokines promote alternative macrophage activation during a TH2 response?

IL – 4 and IL – 13

What is the major outcome of alternative macrophage activation in the TH2 pathway?

Enhanced tissue repair and fibrosis

Which TH2 cytokines stimulate increased intestinal mucus secretion and peristalsis?

IL-4 and IL-13

What is the function of increased intestinal mucus secretion during parasitic worm infections?

It contributes to host defense by helping remove intestinal parasites

What is the role of increased intestinal peristalsis during parasitic worm infections?

Increased intestinal movement helps expel parasitic worms from the gastrointestinal tract

Which cytokine is primarily responsible for eosinophil activation in the TH2 response?

IL- 5

What is the function of eosinophils during TH2 mediated immunity?

They contribute to the destruction of parasitic worms through the release of granule contents

Which cells release cytokines that contribute to the TH2 associated antibody production?

TH2 cells, with TFH cells also shown assisting B lymphocytes

What type of macrophage activation is associated with TH2 responses?

Alternative macrophage activation, which promotes tissue repair and fibrosis (M2)

Which cytokine drives differentiation of antigen activated CD4 T cells into TH2 cells?

IL-4

Which transcription factor is the master regulator of TH2 differentiation?

GATA-3

Which STAT protein is involved in TH2 differentiation?

STAT6

What is the role of Dendritic cells during TH2 differentiation?

Dendritic cells present parasites associated antigens to T lymphocytes, supporting antigen dependent activation and differentiation

What is the relationship between IL-4, STAT6, and GATA-3?

IL-4 promotes STAT6 signaling, which supports GATA -3 associated differentiation of antigen activated CD4+ T cells into TH2 cells

Which cytokines are products of Th1 cells during intracellular infection?

IFN-γ and TNF

What effect do Th1-derived IFN-γ and TNF have on macrophages?

They promote macrophage activation and cell-mediated immunity

Which cytokines are products of Th2 cells?

IL-4 and IL-13

How do Th2-associated IL-4 and IL-13 affect macrophage antimicrobial activity?

They inhibit the microbicidal activity associated with classically activated macrophages

Why can a Th2-dominant response be less effective against certain intracellular pathogens?

Th2 cytokines favor an alternative macrophage response rather than the classical microbicidal activity required to eliminate many intracellular organisms

What are the contrasting macrophage-related outcomes of Th1 and Th2 responses?

Th1 promotes classical macrophage activation and microbial killing, whereas Th2 favors an alternative activation program that can reduce classical microbicidal activity.

What immune response is associated with recovery from Leishmania major infection in most mouse strains?

A Th1-dominant response

What is the typical outcome of Leishmania major infection in most mouse strains with a Th1 response?

Recovery

Which mouse strain is identified as developing a Th2-dominant response to Leishmania major?

BALB/c mice.

What is the outcome of Leishmania major infection in BALB/c mice exhibiting a Th2 response?

Disseminated (spread) infection

Which form of leprosy is associated with a Th1 response to Mycobacterium leprae?

Tuberculoid leprosy.