*Stimulating the Adaptive Immune Response

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What is the humoral immune response?

Immune components in the plasma (antibodies, complement)

What is the cell-mediated immune response?

Leukocytes that directly attack pathogens. (macrophages, cytotoxic T-cells)

What are the 4 subtypes of mature T-cells + their CD markers?

T-helper 1 (Th1) — CD4

T-helper 2 (Th2) — CD4

Regulatory T-cell (Treg) — CD4 + CD25

Cytotoxic T-cell (Tc/CTL) — CD8

What is the primary function of Th1?

• Combats intracellular pathogens

• Activates other CD4 and CD8 cells

• Involved in cell-mediated immunity

• Primary receptor: CD4

What cytokines does Th1 secrete?

• Secretes IL-2 to stimulate other T-cells (CD8 and CD4)

• Secretes TNF-α and INF-γ to stimulate cytotoxic T-cells and macrophages

What is the primary function of Th2?

• Combats extracellular pathogens

• Primary receptor: CD4

• Involved in humoral immunity

What cytokines does Th2 secrete?

Secretes IL-4, -5, -6, -10 → B-cell activation to generate antibodies.

What do cytotoxic T-cells do?

• Destroy cells that have intracellular pathogens.

• Involved in graft rejection

• Required MHC-I for function

What does Th17 do?

Secretes IL-17 and IL-21.

Considered pro-inflammatory and stimulates neutrophil recruitment.

What are memory T-cells?

Long-lived cells to confer long-term immunity.

What do Tregs do?

Secrete IL-10 which suppresses the immune response.

Involved in the development of immune tolerance.

FoxP3 is a marker for Tregs.

Describe the sequence of events in T-cell dependent B-cell activation (7 steps)

1. DC recognizes and phagocytoses pathogen

2. DC migrates to lymphnode and activates naive Th cell

3. APC secretes IL-4 to start Th2 differentiation; IL—2 promotes clonal expansion

4. Antigen binds BCR and is presented on MHC-II

5. Th2 synapses with B-cell and secretes IL-4, -5, -6. -10

6. B-cell is fully activated

7. B-cell differentiates into plasma cells and memory cells

What are the two events required for B-cell activation in a T-dependent response?

1. They must meet the antigen that is specific to the B-cell receptor (antigen will be phagocytosed and presented on MHC-II)

2. They must meet a Th2 cell that is also specific to this antigen and will ultimately activate the B-cell

→ Prevents inappropriate antibody production

What is clonal expansion and when does it occur?

• The proliferatoin of antigen-specific lymphocytes.

• Starts when Th2 cells recognize antigen and stimulate their own proliferation via IL-2.

• On activation, B-cells also divide to produce a clonal population that recognizes the same antigen.

What cytokine drives Th1 differentiation and what is its source?

IL-12 or IL-1 drives Th1 differentiation. Occurs when APC phagocytose damaged cells displaying DAMPs.

What are the two main functions of Th1 cells in cell mediated immunity?

1. Secretes IL-2 and other cytokines to induce cytotoxic T-cell proliferation and activation

2. Secrete TNF-α and IFN-γ to stimulate macrophages at the site of infection

How to cytotoxic T-cells recognize infected cells?

1. All cellular proteins are displayed by MHC-I

2. CD8 proteins bind to MHC-I on target cell

3. TCR recognizes presented viral/abnormal antigens

4. If recognizes, cytotoxic T-cell attacks infected cell.

What are the 3 methods cytotoxic T-cells use to kill target cells?

Perforin — structurally related to complement C9; permeablizes membrane → lysis

Granzyme — serine esterases that induce apoptosis and DNA degradation

Fas ligand (FasL) — when interacts with FasR, it signals that cell to die

What are the major functions of the cell-mediated response?

1. Destruction of cells infected with intracellular microbes

2. Defense against fungi, protozoa, and parasites

3. Graft rejection

4. Destruction of tumor cells

What are the 4 other killer cells and their characteristics?

Cytotoxic T-cells (CTL) — antigen specific, kills target cell with perforin/granzyme/FasL

Natural Killer (NK) cells — non-specific (TLR) innate immune cell, kills target with perforin/gramzyme/FasL

Lymphokine Activated Killer Cells (LAK) — lab-generated NK cells that are induced by IL-2 and target tumor cells

Natural Killer T-cells (NKT) — antigen specific but do not use MHC

What is the difference between T-dependent and T-independent humoral responses?

T-dependent — A B-cell waits until it is activated by the Th cell.

T-independent — activate B-cells without Th stimulation

Describe key features of TI-1 response

B-cell mitogens that induce B-cell division without antigen specificity.

• binds to both TCR and BCR

• no memory cells generated

• works in athymic ppl

• can activate multiple B-cells at high concentrations

Ex. bacterial LPS

Describe key features of TI-2 response

Molecules with highly repetitive structure like capsule.

• cross-links B-cell receptor on surface of mature B-cell

• only activates mature B-cells 

• functional in athymic ppl

• no memory cells generated

Ex. flagella

Why do we need TI responses?

• is a response to non-protein antigens that are not as effective when activating a TD response

• rapidly responding to pathogens to slow down disease progression

• additional layer of protection, complementing TD response

• an early response in newborns with immature TD response

What are superantigens?

Molecules that activate Th cells even if they don’t fit the TCR

• binds MHC-II and TCR together, resulting in activation of 2-20% of Th cells → overproduction of cytokines

A loophole in immune response.

What is an immune checkpoint and when does it engage?

Acts as brakes or checkpoints to prevent immune system from attacking normal, healthy cells.

Engages when receptors on surface of T-cells bind to partner proteins on other cells.

Tells T-cells to ignore antigen. Important for self-tolerance.

Relate cancer cells and immune checkpoints

Cancer cells are human cells that highjack checkpoint pathways to avoid beingn attacked. 

Checkpoint inhibition is cancer immunotherapy approach; blocks receptors that signal T-cells to ignore cancer cells.

What is CTLA4?

Cytotoxic T-lymphocyte-associated protein 4

An immune checkpoint inhibitor, to combat we use anti-CTLA4.

What is PD-1?

An inhibitory receptor found on surface of T-cells.

When it interacts with PD-L1 receptor on cells, T-cells are suppressed.

Cancer cells espress PD-L1. Reversed by blocking PD-L1

What are CAR-T cells?

CAR = chimeric antigen receptor

B-cells are sequence and cloned into a T-cell as ‘chimeric’ TCR

Genetically modified to ID specific cells → targeted destruction of cancer cells

T-cells selected with anti-CD3/CD28 antibody coated beads. Grown in lab with IL-2 then infused back into patient.