BACHELOR OF SCIENCE IN BIOLOGY:
IMMUNOLOGY
COURSE MODULE
COURSE UNIT
WEEK
7
2
8
EFFECTOR FUNCTIONS OF T CELL-MEDIATED IMMUNITY
✓ Read course and unit objectives
✓ Read study guide prior to class attendance
✓ Read required learning resources; refer to unit
terminologies for jargons
✓ Proactively participate in classroom discussions
✓ Participate in weekly discussion board (Canvas)
✓ Answer and submit course unit tasks
At the end of this unit, the students are expected to:
Cognitive:
1.
2.
3.
4.
5.
Identify the different types of cell mediated immune reactions
Explain the migratory activities of T cells in response to an infection
Explain the functions of the CD4+ helper T lymphocytes
Explain the function of CD8+ cytotoxic T lymphocytes
Understand the mechanism of occurrence of resistance of pathogenic microorganisms to cell
mediated immunity
Affective:
1. Inculcate importance of a reward system in organizations
2. Listen attentively during class discussions
3. Demonstrate tact and respect when challenging other people’s opinions and ideas
4. Accept comments and reactions of classmates on one’s opinions openly and graciously.
Psychomotor:
1. Participate actively during class discussions
2. Confidently express personal opinion and thoughts in front of the class
Code of Ethics:
1. Submit assessment tasks and other required outputs with honesty and integrity.
Abbas, A. K., Lichtman, A. H., & Pillai, S. (2020). Basic immunology E-book: Functions and disorders of
the immune system.ch.6. Elsevier Health Sciences.
TYPES OF T CELL-MEDIATED IMMUNE REACTIONS
• Recruitment and activation of phagocytes by CD4+ helper T cells to kill ingested and some
extracellular microbes
o CD4+ T cells
▪ Recognize antigens of microbes in phagocytic vesicles ➔ secrete cytokines ➔
recruit and activate leukocytes ➔ leukocytes kill microbes
• Eradication (killing) of infected cells containing microbial proteins in the cytosol or nucleus which
is accomplished by CD8+ cytotoxic T lymphocytes (CTLs)
T cell antigen recognition:
• CD4+ T cells
o recognize antigens of microbes ( intracellular or extracellular ) internalized into endocytic
vesicles.
• CD8+ T cells
o recognize microbial antigens that are present in the cytosol of infected cells and destroy
these cells.
MIGRATION OF T LYMPHOCYTES IN CELL-MEDIATED IMMUNE REACTIONS
• MIGRATORY ACTIVITIES OF T CELLS (mediated by adhesion molecules and chemokine
receptors)
o Migration of naïve T cells between blood and lymphoid tissues
▪
o
•
Antigen presentation by dendritic cells within a lymph node or spleen ➔ antigen
recognition by T cells ➔ T cell activation and differentiation into expanded
clones of effector T cells
Migration of effector T cells back to the site of infection in peripheral tissues
MIGRATION OF NAÏVE T CELLS
o Migrate into lymph nodes through high endothelial venules (HEVs)
o Mediated by:
▪ adhesion molecule : L-selectin (CD62L)
▪ Chemokine receptor: CCR7
o
Migration of naïve T cells into the lymph nodes
▪ Naïve T cell + L selectin ➔ rolling interactions with HEVs ➔ chemokines bind to
CCR7 ➔activation of LFA-1 ➔naïve T cell binds tightly to ligand,
INTRACELLULAR ADHESION MOLECULE 1 (ICAM-1) on the HEV ➔ T cells
exit HEV ➔ remain in the T cell zone of the lymph node
o
Sphingosine 1-phosphate
▪ Role in T cell exit from lymph nodes
▪ Binds to receptor S1PR1
If T cell does not recognize an antigen
▪ Leaves the node through efferent lymphatic vessels
If T cell recognizes antigen
▪ T cell remains in the lymph node to undergo clonal expansion and differentiation
▪ T cell activation
After clonal expansion and differentiation
▪ Decrease expression of L-selectin and CCR7 ➔ exit of T cells into the circulation
o
o
o
o
Effector T cell migration to site of infection in peripheral tissues
▪ Mediated by adhesion molecules, E-selectin and P-selectin, integrins and
chemokines secreted on the vascular endothelium at the inflammatory sites
▪ Independent of antigen recognition
▪ Effector T cells passing through blood vessels bind to endothelial selectins ➔
rolling ➔chemokine recognition ➔ binding of integrin to their ligands ➔
adhesion of T cells to endothelium ➔ T cell migration to site of infection
EFFECTOR FUNCTIONS OF CD4+ HELPER T LYMPHOCYTES
Subsets of CD4+ helper T cells
• Th1 subset of CD4+ helper T cells
o Recognize antigens of pathogens
o induced by microbes that are ingested by and activate phagocytes, primarily
macrophages
o stimulate phagocyte-mediated killing of ingested microbe
o activate macrophages by expressing CD40 ligand and secreting IFN gamma (Classical
Macrophage Activation)
o ingested pathogens ➔ enclosed in phagosomes ➔ microbial peptides displayed by
class II MHC molecules on macrophage surface ➔effector CD4+ T cells recognize class
II associated peptides ➔ T lymphocytes express CD40 ligands ➔ bind to CD40 receptor
on the macrophages ➔ T cells also secrete IFN gamma which binds to its receptors on
macrophages ➔activation of transcription factors ➔ macrophages produce microbicidal
substances ➔ killing of phagocytized bacteria
o activated macrophages secrete cytokines (TNF, IL-1 and chemokines) which induce
inflammation, promote fibrosis and tissue repair.
o Development of Th1 Cells
▪ Intracellular bacteria and viruses stimulate dendritic cells and macrophages to
produce IL-12 and NK cells to produce IFN-γ
▪ IL-12 activates the transcription factor Stat4.
▪ IFN-γ activates the transcription factor Stat1.
▪ antigen-induced signals plus cytokines induce expression of a transcription factor
called T-bet
▪ Above transcription factors promote Th1 development.
▪ IFN-γ
• Activates macrophages to kill ingested microbes
• Promotes Th 1 development
• Inhibits development of Th2 and Th17
•
Th17 subset
o develop in response to extracellular bacterial and fungal infections
o major cytokines produced: IL-17 and IL-22
o functions:
▪ Enhance recruitment of neutrophils and monocytes by inducing other cells to
secrete cytokines causing inflammation
▪ Stimulate the production of defensins (antimicrobial substances)
▪ Help maintain the integrity of epithelial barriers by secreting cytokines
o Development of Th17 cells
▪ Dendritic cells and macrophages produce cytokines in response to fungi and
extracellular bacteria
• Cytokines
o IL-1, IL-6, and IL-23
▪ IL-6 and IL-23 activate the transcription factor Stat3.
innate inflammatory cytokines and transforming growth factor β (TGF-β), plus
TCR signals, stimulate the expression of the transcription factor RORγT.
Defects in Th17 responses
▪ May lead to bacterial abscesses and chronic mucocutaneous candidiasis
▪
o
•
Th2 subset
o Functions:
o Stimulate eosinophilic inflammation
o Defense against helminthic infections
1. antigen recognition by Th2 cells
2. production of IL-4 ➔ stimulates IgE production ➔ binds to Fc receptors on
mast cells and eosinophils
3. production of IL-5 ➔ activates eosinophils ➔ granule protein of eosinophils kill
Heminths
4. cytokines stimulate mucus secretion and peristalsis in intestinal tract ➔
expulsion of helminths from gut
o Secrete cytokines that inhibit classical macrophage activation (IL-4 & IL-10) and
stimulate the alternative pathway of macrophage activation (IL-4 & IL-13)
o Alternative pathway of macrophage activation
▪ Role in tissue repair
▪ Fibrosis and tissue damage in chronic parasitic infections and allergic
disease
o Development of Th2 subset
o Mast cells produce IL-4 during helminth infection.
o IL-4 activates transcription factor Stat6.
o Antigen-induced signals plus IL-4 induce expression of a transcription factor
GATA-3.
o These transcription factors cause Th2 differentiation .
EFFECTOR FUNCTIONS OF CD8+CYTOTOXIC T LYMPHOCYTES
o Recognize class I MHC-associated peptides on infected cells which leads to elimination or
killing of these cells.
o Sources of peptides
▪ Protein antigens synthesized in the cytosol
▪ Antigens that escape from phagocytic vesicles into the cytosol
o Sequence of events:
1. CTLs recognize class I MHC-peptide complexes on infected cell surface (targets of CTLs)
through TCR and CD8 coreceptor
2. TCR, CD8 and other signaling proteins cluster in the CTL membrane and be come
surrounded by adhesion molecules (LFA-1 integrin) forming an immunologic synapse
3. CTL’s secrete cytotoxic proteins
4. Signal transduction pathways are activated
5. Exocytosis of the contents of the CTL’s granules into the immune synapse between CTL and
target cell
o
Granule proteins
o Granzymes
▪ Granzyme B
• Cleaves and activates caspases in the cytosol of target
cells
• Induces apoptosis
o Perforin
• Disrupts the integrity of the target cell plasma membranes
and endosomal membranes
o Facilitates delivery of granzymes into the cytosol to
induce apoptosis
6. Activated CTLs also express membrane protein Fas ligand
•
Fas ligand ➔ binds to Fas (CD95) receptor ➔activates caspases ➔ induces apoptosis
7. Cells which have undergone apoptosis are phagocytized and eliminated
MODES OF RESISTANCE OF PATHOGENS TO CELL MEDIATED IMMUNITY
•
Inhibition of fusion of phagosomes with lysosomes
•
Escape of pathogens from phagocytes into the cytosol
•
Inhibition of production or expression of class I molecules
•
Inhibition of class I MHC-associated antigen presentation
•
Blockage of transport of antigenic peptides from the cytosol into the endoplasmic
•
reticulum
•
Defective loading of class I MHC molecules by viral peptides
•
Production of inhibitory cytokines or soluble (decoy) cytokine receptors
•
Inhibition of effector function of CTL by stimulation of the expression of inhibitory
receptor PD-1 on CD8+ T cells
•
Direct infection and destruction of T lymphocytes (HIV)
Answer the following questions:
1. Explain why individuals with inherited defects in the development and function of Th1 cells are
susceptible to infections caused by bacteria (such as atypical mycobacteria) which are usually
harmless.
2. Explain how T cells activate macrophages. How do macrophages respond to activation by T cells?
Explain.
3. Explain why differentiated effector T cells migrate to tissues which are sites of infection and not to
lymph nodes.
4. Explain how CD4+ and CD8+ T cells cooperate to eradicate intracellular infections.
Abbas, A. K., Lichtman, A. H., & Pillai, S. (2020). Basic immunology E-book: Functions and disorders of
the immune system.ch.6. Elsevier Health Sciences.
Co-receptors: Function. (n.d.). British Society for Immunology |. https://www.immunology.org/publicinformation/bitesized-immunology/systems-and-processes/co-receptors-function
Overview of T cell subsets. (2018, May 3). Immunopaedia | Advancing global immunology
education. https://www.immunopaedia.org.za/immunology/basics/5-overview-of-t-cell-subsets/