Cellular Immune Responses

What is cell-mediated immunity (CMI)?

Defense against microbes mediated by T cells, crucial for eliminating intracellular pathogens.

What are the phases of cell-mediated immunity?

1. Induction Phase – Antigen recognition in lymphoid organs → T cell expansion & differentiation.

2. Effector Phase – Migration of effector T cells to infection site → Activation & elimination of microbes.

What happens after T cells recognize an antigen?

They expand, differentiate into effector T cells, and enter circulation to locate infection sites.

How do CD4+ T cells contribute to immunity?

• Differentiate into CD4+ effector T cells → Enter circulation.

• Encounter intracellular microbes → Release cytokines.

• Cytokines trigger inflammation, enhance phagocytosis, and help kill microbes.

How do CD8+ T cells contribute to immunity?

• Naïve CD8+ T cells activate in lymphoid organs → Differentiate into Cytotoxic T lymphocytes (CTLs).

• CTLs migrate to infection sites and directly kill infected cells.

What is the primary function of CD4+ effector T lymphocytes?

They secrete cytokines to activate leukocytes and stimulate antibody production.

What is the primary function of CD8+ effector T cells?

They kill infected cells and tumor cells directly.

How do CD4+ Th1 cells help eradicate infections?

• Bind to macrophages containing ingested microbes.

• Secrete cytokines (e.g., IFN-γ).

• Activate macrophages → Enhance killing of ingested microbes.

How do CD4+ Th17 cells help fight infections?

• Bind to macrophages containing microbes.

• Secrete cytokines that promote inflammation.

• Inflammation enhances microbe killing.

What happens when a cell is infected with microbes or antigens in the cytoplasm?

CD8+ T cells (CTLs) recognize the infected cell and kill it.

What is the function of TCR, and what is its ligand?

Function: Antigen recognition
Ligand: Peptide-MHC

What is the function of CD4, and what is its ligand?

Function: Signal transduction
Ligand: Class II MHC (on APCs)

What is the function of CD8, and what is its ligand?

Function: Signal transduction
Ligand: Class I MHC (on all nucleated cells)

What is the function of CD28, and what is its ligand?

Function: Signal transduction (costimulation)
Ligand: B7-1/B7-2 (on APCs)

What is the function of CTLA-4, and what is its ligand?

Function: Negative regulation
Ligand: B7-1/B7-2 (on APCs)

What is the function of PD-1, and what is its ligand?

Function: Negative regulation
Ligand: PD-L1/PD-L2 (on APCs, tissue cells, tumor cells)

What is the function of LFA-1, and what is its ligand?

Function: Adhesion
Ligand: ICAM-1 (on APCs, endothelium)

What are the key steps in the CD4+ T cell–mediated immune response?

1. Antigen Recognition & Induction – Naive CD4+ T cells recognize antigens in lymphoid organs.

2. T Cell Activation – Dendritic cells release cytokines, and costimulatory signals (B7-CD28) activate CD4+ T cells.

3. Proliferation & Differentiation – Activated CD4+ T cells multiply and differentiate into effector Th cells.

4. Migration to Infection Site – Effector T cells, neutrophils, and monocytes enter circulation and move toward infection.

5. Effector Functions at Infection Site –

   • Macrophage Activation → Phagocytosis & microbial killing.

   • Neutrophils & Monocytes → Inflammation & leukocyte activation.

What is the role of ICOS (Inducible Costimulator) in T cell function?

• ICOS is homologous to CD28 and is expressed on T cells.

• It plays an important role in the development and function of follicular helper T cells (Tfh cells) during germinal center responses.

• ICOS binds to its ligand ICOSL (expressed on B cells and APCs) to enhance the function of Tfh cells, promoting B cell activation and antibody production.

What types of microbes stimulate the development of Th1 cells?

stimulated by intracellular bacteria (e.g., Listeria, mycobacteria) and parasites (e.g., Leishmania) that infect dendritic cells (DCs) and macrophages.

What cytokines stimulate the differentiation of Th1 cells?

IFN-γ and IL-12 stimulate the differentiation of Th1 cells.

Which transcription factors are activated for Th1 differentiation?

• T-BET

• STAT1

• STAT4

Which microbes survive within phagolysosomes of phagocytes?

• Intracellular bacteria: Mycobacteria, Listeria monocytogenes, Legionella pneumophila

• Fungi: Cryptococcus neoformans

• Protozoa: Leishmania, Trypanosoma cruzi

Which microbes infect nonphagocytic cells, such as epithelial cells?

• Viruses: Various viruses, including Rickettsiae

• Protozoa: Plasmodium falciparum, Cryptosporidium parvum

What are the key effects of Th1-mediated classical macrophage activation?

• Production of reactive oxygen species (ROS), nitric oxide, and increased lysosomal enzymes: This leads to the killing of microbes in phagolysosomes (effector function of macrophages).

• Secretion of cytokines (TNF, IL-1, IL-12) and chemokines:

  • TNF and IL-1: Involved in leukocyte recruitment and inflammation.

  • IL-12: Promotes Th1 differentiation and IFN-gamma production.

• Increased expression of B7 costimulators and MHC molecules: Enhances T cell activation and amplifies the T cell response.

What are the other effector functions of Th1 cells?

• IFN-γ: Promotes Th1 differentiation and inhibits the development of Th2 and Th17 cells.

• TNF (Tumor Necrosis Factor): Contributes to the recruitment of leukocytes.

• Excessive Th1 reactions: Can cause tissue injury in chronic inflammatory diseases.

• IL-10 production: Th1 cells produce IL-10, which inhibits dendritic cells (DCs) and macrophages, leading to suppression of Th1 activation.

  • This IL-10 production creates a negative feedback loop in T cell responses.

How are Th2 cells developed?

Th2 cells are developed in response to helminths and allergens, particularly in mucosal tissues, and are involved in IgE-mediated defense mechanisms using eosinophils and mast cells.

• Cytokine IL-4 plays a key role in Th2 differentiation.

• IL-4 activates the transcription factor STAT6, which, together with TCR signals, induces expression of the transcription factor GATA3.

• GATA3 blocks Th1 differentiation by inhibiting the expression of the IL-12 receptor's signaling chain.

What are the IL-4-dependent functions of Th2 cells?

IL-4 and IL-13 contribute to the following Th2 cell functions:

• Alternative macrophage activation

• Stimulation of peristalsis in the gastrointestinal tract

• Increased mucus secretion from airway and gut epithelial cells (via IL-13)

• Recruitment of eosinophils (IL-5)

What are the other effector functions of Th2 cells?

• IL-13 and IL-4 activate B cells to switch to IgE and some IgG isotypes.

• IgE coats mast cells and induces their degranulation upon antigen encounter.

• IL-5 activates eosinophils and links T cell activation to eosinophilic inflammation.

• Eosinophils express Fc receptors for IgA and IgG antibodies, enabling them to help fight helminths.

What is involved in the development of Th17 cells?

• Th17 cells are primarily involved in recruiting neutrophils.

• They are stimulated by proinflammatory cytokines produced in response to bacteria and fungi.

• IL-6, IL-1, and IL-23 promote Th17 differentiation.

• TGF-β along with IL-6 and IL-1 activate the transcription factors RORγt (RORc) and STAT3.

• IL-23 stabilizes the Th17 subset

What are the IL-17-dependent functions of Th17 cells?

• IL-17 is a crucial link between T cell–mediated adaptive immunity and the acute inflammatory response.

• IL-17 stimulates the production of chemokines (e.g., IL-8) and other cytokines (e.g., TNF) that recruit neutrophils.

• IL-17 enhances neutrophil generation by increasing the production of granulocyte colony-stimulating factor (G-CSF).

• IL-17 stimulates the production of antimicrobial substances, such as defensins.

What are the other effector functions of Th17 cells?

• IL-22 is produced by Th17 cells in epithelial tissues (skin and gastrointestinal tract) and contributes to inflammation by stimulating epithelial production of chemokines.

• IL-21 stimulates the generation of Tfh cells and activates B cells in germinal centers.

• IL-21 can increase the proliferation, differentiation, and effector function of CD8+ T cells and NK cells.

• Th17 responses are associated with psoriasis, inflammatory bowel disease, rheumatoid arthritis, and multiple sclerosis.

What is the process of differentiation of CD8+ T cells into cytotoxic T lymphocytes (CTLs)?

• Dendritic cell presents antigen to a naive CD8+ T cell in the lymph node, along with costimulation.

• T cell proliferation occurs, leading to the differentiation of CD8+ effector T cells (CTLs).

• Differentiated CTLs enter circulation and migrate to the site of infection.

• CTLs recognize and kill infected tissue cells, eliminating the pathogen

How do CD4+ helper T cells aid in CD8+ T cell differentiation?

1. CD4+ helper T cells produce IL-2, which stimulates CD8+ T cell proliferation and differentiation.

2. CD4+ helper T cells activate APCs via the CD40-CD40L interaction, enhancing their ability to activate CD8+ T cells.

3. IL-12 and type I IFNs from APCs promote CTL differentiation.

4. APCs with costimulators interact with naive CD8+ T cells, driving their differentiation into CTLs and memory CD8+ T cells.

CD8+ CTL Killing Mechanisms: Perforin/Granzyme & FAS/FASL Pathways

Perforin/Granzyme-Mediated Killing:

1. CD8+ CTL binds to target cell via CD8-MHC I and LFA-1-ICAM-1 interactions.

2. Granule exocytosis: CTL releases perforin & granzymes into the immune synapse.

3. Perforin forms pores in the target cell membrane.

4. Granzymes enter the target cell, activate caspases.

5. Apoptosis of the target cell.

FAS/FASL-Mediated Killing:

1. CD8+ CTL expresses FASL, target cell expresses FAS receptor.

2. FASL binds to FAS, leading to recruitment of caspase-activating proteins.

3. Caspases are activated, initiating the apoptotic pathway.

4. Target cell undergoes apoptosis.

What are the two main mechanisms CD8+ CTLs use to kill infected cells?

• Perforin-Granzymes Pathway:

  • Perforin (C9 complement-like protein) forms pores in the target cell membrane.

  • Granzymes (serine proteases) enter through pores, activating caspases → Apoptosis.

• FAS-FASL Pathway (Granule-Independent):

  • FASL (on CTL) binds to FAS (on target cell).

  • Activates caspases, leading to Apoptosis.

Comparison: SMAC in T Helper Cells vs. KISS OF DEATH in CTLs

SMAC (Supramolecular Activation Cluster) in T Helper Cells:

1. Scanning: T helper (Th) cell binds to B cell → Synapse formation
2. Mature Synapse: Stable interaction leads to cytokine production
3. Synapse Dissolution: Th cell detaches after signal delivery
4. Proliferation: B cell activation & proliferation

KISS OF DEATH in Cytotoxic T Cells (CTLs):

1. Scanning: CTL binds to the target cell (immune synapse forms)

2. Mature Synapse: CTL aligns lytic granules at synapse

3. Cytotoxic Effector Mechanism:

• Granules release perforin & granzymes into the sMAC (secretory microtubule-activating center)

• Induces apoptosis of the target cell

• 4. More Killing: CTL detaches and moves to new target cells.