6. Adaptive Immunity II- Antigen Presentation and Th Cell Subsets

State the different categories of lymphocytes.

• Immature cells

• Naïve cells

• Activated cells

• Effector cells

• Memory cells

What is an immature cell?

Cells that have not fully developed their antigen-specific receptors.

What is a naïve cell?

• A cell containing antigen receptors but has yet to encounter an antigen to which they were programmed to respond.

• They are fully mature but are naïve to antigens.

What is an activated cell?

• Cells able to proliferate

• Contain bound antigens

• Receive accessory signals from other cells.

What is an effector cell?

• Derived from ‘activated cells’

• Can produce cytokines or other substances

• Have effector functions

What is a memory cell?

• Long-lived descendants of activated lymphocytes.

• Can quickly revert into an activated cell.

How do dendritic cells mature?

Dendritic cells recognise antigens and PAMPs in the periphery via TLRs.

What do mature dendritic cells secrete? What does this do?

B7 molecules (B7.1 and B7.2), granting cells the ability to stimulate T cells. Thus, these cells are vital for the initial activation of T helper and cytotoxic cells.

What do migratory dendritic cells do?

Once antigen-presenting, dendritic cells migrate to the lymphoid organs and transfer antigens to resident dendritic cells there.

What cell express both MHC class glycoproteins?

• Dendritic cells

• Macrophages

• B cells

How do cell-adhesion molecules mediate the initial interaction of naïve T cells with APCs?

• T cells transiently interact with all APCs they find.

• Low affinity interactions between T cells and APCs are mediated by adhesion molecules.

• This slows the interaction down, enabling sufficient time to check for cognates.

State the adhesion molecules on T cells.

• LFA-1

• CD2

State the adhesion molecules on APCs.

• ICAM-1

• ICAM-2

• CD58

What happens to LFA-1 following a cognate discovery?

• APC: T cell complex signals to LFA-1 to undergo a conformational change.

• This transforms the low affinity interaction to a high affinity one, stabilising the interaction (clamps down on the adhesion molecule on TCR).

• This prolongs APC:T cell contact.

State the three signals from dendritic cells that are required to activate naïve T cells. Why are all three signals necessary for naïve T cell activation?

• Antigen presentation

• B7.1 (CD80) and B2.7 (CD86)

• Cytokines

• Signal 1 alone: Leads to partial activation.

• Signal 1 + Signal 2: Supports survival and proliferation without functional specialization.

• Signal 1 + Signal 2 + Signal 3: Ensures full activation, survival, and differentiation into appropriate effector subtypes.

What is the outcome of antigen presentation in naïve T cells?

Activation and initiation of intracellular signalling within the T cell.

What is the effect of the B7.1 (CD80) and B7.2 (CD86) signals on T cells?

T cell survival and proliferation. Without it, T cells become anergic or undergo apoptosis.

What is the first signal required for naïve T cell activation?

Antigen presentation through the TCR recognising a specific antigen bound to MHC on an APC (MHC-I for CD8+ and MHC-II for CD4+).

What is the second signal required for naïve T cell activation, and what molecules are involved?

Costimulation provided by B7.1 (CD80) and B7.2 (CD86) on APCs binding to CD28 on T cells, a co-stimulatory receptor on naïve T cells.

What is the third signal required for naïve T cell activation, and what molecules are involved?

Cytokines secreted by APCs, such as IL-12, IL-4, IL-6, and TGF-β.

What is the effect of cytokines on T cell activation?

Provides immunological context. Cytokines guide T cell differentiation into specific effector subtypes like Th1, Th2, Th17, or Treg cells.

Generally speaking, what happens after T cell activation?

• Rapid T cell proliferation

• Further activation of T cells by macrophages and B cells

• B cell antigen internalisation and presentation

How does IL-2 promote rapid proliferation?

• A naive T cell has a moderate affinity to IL-2.

• Once activated, the T cells have a high affinity for IL-2 (joining of the alpha subunit), creating an IL-2 receptor.

• Dendritic cells and T cells can remain locked together for days.

• IL-2 modulates T cell differentiation and enhances proliferation.

What cells are sensitive to IL-2?

T regulatory cells. Perhaps IL-2 is important for T regulatory cell regulation.

What is the function of the IL-2 receptor?

• Recognise and bind IL-2.

• Decides the balance between effector and regulatory cell production.

How do macrophages and B cells further activate T cells?

• Activated B cells express B7.1/B7.2 after binding to antigens.

• Activated macrophages express B7.1/B7.2 by microbial products and cytokines.

• B cells and macrophages expand the ongoing response by stimulating CD4 T helper cells.

Why do macrophages not activate naive T cells?

Their primary function is tissue homeostasis, producing lots of self antigens. The adaptive immune response would always be set off if they activated T cells.

Compare how macrophages and B cells express MHC.

• Macrophages do not express lots of MHC unless PAMPs activate them.

• B cells express high levels of MHC all the time (B7 mainly).

Describe the process of B cell antigen internalisation and presentation.

• B cells use their surface immunoglobulins to bind antigens.

• Specific antigen is efficiently internalised by receptor-mediated endocytosis.

• A high density of specific antigen fragments is presented at the B cell surface.

Describe antigen uptake in the three main antigen presenting cells.

• Dendritic cells- via macropinocytosis and phagocytosis by tissue dendritic cells.

• Macrophages- via macropinocytosis and phagocytosis.

• B cells- via antigen-specific receptor (Ig)

Describe MHC expression in the three main antigen presenting cells.

• Dendritic cells- low on tissue-resident dendritic cells; high on dendritic cells in lymphoid tissues.

• Macrophages- inducible by bacteria and cytokines.

• B cells- express MHC constitutively at fairly high levels but further increases upon activation.

Describe co-stimulation delivery in the three main antigen presenting cells.

• Dendritic cells- inducible; high on dendritic cells in lymphoid tissues.

• Macrophages- co-stimulatory molecule expression is either absent or minimal; expression of co-stimulatory molecules is significantly up-regulated upon activation.

• B cells- co-stimulatory molecule expression is either absent or minimal; expression of co-stimulatory molecules is significantly up-regulated upon activation.

Describe the location of the three main antigen presenting cells.

• Dendritic cells- ubiquitous throughout the body.

• Macrophages- lymphoid tissue, connective tissue, body cavities.

• B cells- lymphoid tissue, peripheral blood

What is the effect of the three main antigen presenting cells?

Dendritic cells- activation of naive T cells.

Macrophages- macrophage activation.

B cell- aids B cell help delivery.

State the different types of CD4 cells.

• Th1

• Th2

• Th17

• T-reg

Describe the functions of Th1 cells.

• Cytotoxic T cell (CD8) and macrophage activation.

• Aid B cells.

• Intracellular pathogen clearance (Listeria, Mycobacterium tuberculosis).

Describe the functions of Th2 cells.

• Aid B cells for antibody production, IgE responses in particular (anything that isn’t easily phagocytosed).

• Control parasitic infections.

• Eosinophil activation.

• Allergen responses.

Describe the function of Th17 cells.

• Neutrophil recruitment.

• Inflammatory reaction regulation.

• Produces lots of IL-17

Describe the functions of T-reg cells.

• Immune response regulation and reduction.

• Promotes tolerance and resolution.

How many types of T helper cells can CD4 differentiate into? What are they?

• Th1

• Th2

• Th17

Which cytokines determine naive T cell differentiation?

• IL-12 induces the Th1 cell differentiation.

• IL-4 and DC induce Th2 cell differentiation.

• IL-6 and IL-23 induce and stimulate Th17 proliferation.

What does IL-12 induce?

Th1 cell differentation.

What do IL-4 and dendritic cells induce?

Th2 cell differentiation.

What does IL-6 and IL-23 induce?

Th17 cell proliferation.

Why are dendritic cells important in naive T cell differentiation?

Secrete cytokines which influence T cell differentiation thus determines the type of immunological response that will be carried out.

How is T cell differentiation segmented?

The production of one cell subtype may have an inhibitory effect on the differentiation of another.

What do the functions of T helper cells depend on?

Depend on the cytokines they secrete.

What does Th1 secrete?

• IL-2

• Interferon-γ (IFN-γ)

What does Th2 secrete?

• IL-4

• IL-5

• IL-6

• IL-10

• IL-13

What does Th17 secrete?

• IL-17

• IL-22

What are the main functions of CD8 cytotoxic T cells? What pathogens do they target?

Main functions: kill virus-infected cells.

Pathogens targeted:

• Viruses

• Some intracellular bacteria.

What are the main functions of CD4 Th1 cells? What pathogens do they target?

Main functions:

• Activate infected macrophages

• Provide help to B cells for antibody production.

Pathogens targeted:

• Microbes persisting in macrophage vesicles.

• Extracellular bacteria

What are the main functions of CD4 Th2 cells? What pathogens do they target?

Main functions: Provide help to B cells for antibody production, especially switching to IgE

Pathogens targeted: Helminth parasites

What are the main functions of CD4 Th17 cells? What pathogens do they target?

Main functions: enhance neutrophil response

Pathogens targeted: Extracellular bacteria (e.g. Salmonella enterica).