Immunology I -ch11

Dendritic Cells (DC)

• Dendritic cells are antigen-presenting cells of the immune system.

• They originate in the bone marrow.

• Their primary function involves processing antigens and presenting them on the cell surface, primarily to CD4 T cells.

• DCs are located in tissues exposed to the external environment, such as the skin and linings of the nose, lungs, stomach, and intestines.

Mechanism of Action of Dendritic Cells

• DCs constitutively express high levels of:

  • MHC class II molecules

  • Co-stimulatory molecules (B7 family).

  • Co-stimulatory molecules are surface molecules that aid in T cell activation. They are co-expressed with MHC complexes on DCs and bind to receptors on T cells to initiate an immune response.

• DCs are considered potent antigen-presenting cells due to:

  • Efficient antigen presentation.

  • Activation of T Helper cells (CD4 T cells) through Signal 1.

  • Expression of co-stimulatory molecules CD80 and CD86, which support T cell proliferation and differentiation (Signal 2).

• Dendritic cells pick up antigens at sites of infection and migrate to secondary lymphoid organs (lymph nodes, spleen).

• Dendritic cells engulf pathogens and degrade them intracellularly.

• This process leads to the display of antigen peptides on MHC molecules of the dendritic cells, enabling CD4 T cell receptors to initiate an immune response.

• The co-stimulatory molecules (CD80, CD86) on DCs support T cells to proliferate and differentiate into their functional, active forms.

T Cell Activation and Co-stimulation

• Co-stimulatory molecules are surface molecules that can modulate the immune response but cannot activate T cells on their own.

• They are activated only after the first signal has occurred.

• Co-stimulatory ligands are present on dendritic cells, macrophages, and B cells.

• Co-stimulatory receptors are present on T cells.

Two-Signal Hypothesis

• Activation of a T cell requires two signals:

  • Signal 1: Antigen-specific T cell receptor (TCR) binding to the MHC:peptide complex.

  • Signal 2: Antigen-independent co-stimulatory receptor interaction.

• This theory suggests that T cells are most efficient when both signals are actively associated through receptor-ligand binding.

Co-Stimulatory Ligands

• Both CD80 and CD86 on antigen-presenting cells interact with T cell receptors CD28 and CTLA-4.

• CD80/CD86 serves as ligands for CD28 and CTLA-4 receptors found on T-cells.

• Interaction of CD80 ligand with CD28 receptor triggers costimulatory signals and results in enhanced T-cell activation.

• Interaction of CD80 with CTLA-4 inhibits T- cell response.

CD4 T Cell Activation

• Interaction of CD4 T cells with the MHC-peptide complex and co-stimulatory molecule (CD28) leads to activation.

• This induces CD4 T cells to enter the cell cycle, proliferate, and differentiate into memory cells or effector cells.

• Once the T cell is activated with Signal 1 (MHC-Peptide complex) and Signal 2 (Co-stimulatory molecule, CD28), it initiates a primary response.

• Signal 1 and 2 triggers:

  • Entry of the T cell into the G1 phase of the cell cycle.

  • Induces cytokine Interleukin-2 (IL-2) expression.

  • The co-stimulatory signal increases the half-life of IL-2 to enhance its production.

• Secretion of IL-2 and its binding to its receptor induces the activated T cell to proliferate and differentiate.

• T cells enter blast phase and undergo repeated divisions, generating a large clone of T cells, which differentiate into memory or effector T-cell populations.

Effector CD4 T Cells

• Effector CD4 T cells promote activation of various immune cells through cytokine release.

• Effector CD4 T cells are short-lived cells.

• They carry out specialized functions such as cytokine secretion and B-cell production.

• Effector CD4 T cells form two subpopulations:

  • TH1 subset: secretes pro-inflammatory cytokines (IL-2, IFN-γ, TNF-α), activates cytotoxic CD8 T lymphocytes, and helps B-cell activation.

  • TH2 subset: secretes anti-inflammatory cytokines (IL-4, IL-5, IL-6, IL-10) to downregulate the immune response.

  • Regulatory T cells (T regs) (TH3 subset).

Memory T Cells

• Memory T cells are antigen-specific T cells that persist long-term after an infection has been eliminated.

• They are long-lived, quiescent cells that respond to a second encounter with the same antigen, generating a secondary response.

• An expanded population of memory T cells remains long after effector T cells have declined.

CD8 T Cell Activation

• Similar to CD4 T cells, CD8 T cells also require two signals for activation:

  • Signal 1: Antigen-specific T cell receptor (TCR).

  • Signal 2: Antigen-independent co-stimulatory receptor–ligand interaction (CD28 on T cell with CD80/86 on Antigen presenting cells (APC).

• The interaction of CD8 T cells with the MHC-peptide complex and co-stimulatory receptor (CD28) leads to activation.

• It induces CD8 T cells to enter the cell cycle, proliferate, and differentiate into memory or effector cells.

• The signal 1 and 2 triggers:

  • Entry of the CD8 T cell into the G1 phase of the cell cycle.

  • Induces cytokine Interleukin-2 (IL-2)release.

  • Secretion of IL-2 and its subsequent binding to its receptor induces the activated CD8 T cell to proliferate and differentiate.

• CD8 T cells enter blast phase and undergo repeated divisions 2–3 times per day for 4–5 days, generating a large clone of T cells, which differentiate into memory or effector T-cell populations.

CD8 T-Cell Cytotoxic Events

• The primary events in CD8 activation include:

  • Conjugate formation.

  • Membrane attack.

  • CD8 dissociation.

  • Target cell destruction.

• The effector phase of a CD8 T cells begins with the binding of target cell (antigen)to the CD8 T cell.

  • Step 1: Antigen-specific CD8 T cells (CTLs) and antigen, interact and undergo conjugate formation.

  • This conjugate formation is initiated with the help of Lymphocyte function-associated antigen 1( LFA-1).

  • LFA-1 persists for only 5–10 min to allow the CD8 T cells to form a strong conjugate with the antigen.

  • Step 2: Formation of a CTL–target cell conjugate leads to release of cytoplasmic granules.

  • Perforins and Granzymes near the junction with the target cell.

  • Perforins then polymerize and insert into the target-cell membrane to form cylindrical pores with an internal diameter of 5–20 nm.

  • Step 3: Granzymes (granzyme B) then enters the cytoplasm of the target cell initiating the fragmentation of the target-cell DNA via apoptosis.

  • Within 5 min of contact, target cells begin to exhibit DNA fragmentation.

  • The target cell dies by apoptosis within few hours of DNA fragmentation.

  • Step 4: The LFA-1 avidity on CTL is downregulated that allows dissociation of the CD8 T cell from the target cell Thos CD8 then goes on to bind to another target cell.

• In some cases,

• In some cases, Fas ligand (FasL) on the CTL binds to Fas (CD95) on the target cell. - This binding results in the activation of caspase-8 which then activates several downstream targets and ultimately leads to apoptosis of the target cell.- Thus, activated CD8 T cells, are able to recognize infected target cells and kill them by inducing apoptosis.