Dendritic Cell Activation & Licensing

Antigen Presenting Cells deliver 3 signals for Clonal Expansion and Differentiation of naive T-cells:

1. Activation 2. Survival 3. Differentiation

Features of MATURE DC:

1. High MHC & Cytokine secretion 2. High Co-stimulatory 3. Antigen Presenter 4. Low Antigen uptake

What is a Memory T-cell?

A long-lived cell with an enhanced ability to react against antigens

What is the "Immune Synapse"?

APC : T-Cell Interaction: 1. LFA-1 + ICAM-1 2. CD4 + MHC-2 or CD8 + MHC-1 3. If TCR engaged, LFA-1 conforms and bonds STRONGER 4. Activation requires 2 signals: 1. TCR + MHC 2. Co-Stimulatory via CD28 5. CD40L is transiently induced via 2nd signal: Increasing B7 expression & APC survival

How is IL-2 receptor expressed in activated T-cells?

Activated T-cells express a High-Affinity IL-2 receptor (IL-2R alpha, beta, gamma chains) Secreting IL-2

What is an APC?

Antigen Presenting Cell which expresses MHC molecule - displaying microbe antigen and co-stimulators required to activate T-cells

What does CD28 (on T-cell) bind to on APC?

B7 - this is the Co-stimulatory signal 2.

Activated T-cell induces expression of ________ IL-2 receptor and _________

High Affinity & T-cell growth IL-2

What are Langerhans cells?

Immature dendritic cells

Effector T-cells recognize antigens in lymphoid organs and peripheral non-lymphoid tissue

True To perform functions that are responsible for elimination of microbes

What does VLA-4 (on T-cell) bind to?

VCAM-1 on activated endothelium

Death of Target cell by CD8 T-cell only occurs:

upon Antigen-specific Recognition Allowing stable pairing & focused release of Effector molecules

Naive T-cell expresses _______ affinity to IL-2

Moderate Affinity

These are the 3 ways in which the Antigen-Specific T-cell receptor controls delivery of effector signal:

1. Induces Tight Binding of Effector cell to target (narrow space created) 2. Focuses delivery - Re-orients the secretory apparatus 3. Triggers Synthesis and/or Release of cytotoxic granules

Features of IMMATURE DC:

1. Low MHC INSIDE - no on surface = Can't stimulate T-cells 2. Don't express Co-stimulatory molecules 3. Poor secretion of Cytokines 4. Relatively non-motile 5. Good at Antigen Accumulation 6. Efficient Endocytosis 7. Allow Antigens to SIT in the lysosomes - protecting from Degradation

What is CTLA-4?

Binds CD28 more avidly than B7 and INHIBITS signals to activated T-cells Makes the activated progeny of a naive T-cell LESS sensitive to stimulation of APC and limit T-cell Proliferation

What does Co-stimulation w/ CD28 (signal 2) induce in activated T-cells?

CD28-dependent Co-stimulation of activated T-cells - Induces Expression of T-cell growth Interleukin-2 and High-Affinity IL-2 Receptor

What does CXCL8 bind to?

CXCL8 - Receptor

Effector T-cells circulating blood - migrate from blood to infected tissue via:

Chemokines (CXCL8) and Adhesion molecules (VLA-4 on effector T-cells) which bind to VCAM-1 on activated Endothelium

Upon Antigen-Specific Recognition, how does CD8 T-cell focus Effector molecules?

Clustering of the T-cell receptors signal a Reorientation of the Cytoskeleton that polarizes the effector cell This focuses Exocytosis of cytotoxic granules at the site of contact with the target cell

What happens to Effector T-cell?

Continues to migrate through lymphatics until the last piece of lymphatic system ends in the blood system again

How does the DC mature?

From a cell designed to capture protein antigen to an Antigen Presenting Cell (APC)

What is a CTL?

Cytotoxic T-Lymphocyte (CD8+)

These are the strongest activators of naive T-cells

Dendritic Cells

When does DC mature?

During migration to the lymph node

Is there a difference in LFA-1 expression b/w naive T-cells vs effector T-cells?

Effector T-cells express LFA-1, 2 - 4X higher than naive cells

What are the Effector functions of T-cells?

Either CTL (cytotoxic T-lymphocyte) or T-helper cell

Where are dendritic cells found?

In most cell tissues of the body - mainly in tissue which has contact with outside Such as the skin, linings of nose, lungs, stomach, intestines.

Where are immature forms of dendritic cells found?

In the blood

What is the initial interaction b/w APC & T-cell?

Initial interaction is b/w Adhesion molecules LFA-1 and ICAM-1

How long does Activation process take?

It may require T-cell:DC interaction for up to 20 hours

What happens when IL-2 binds to its receptor?

It signals the T-cell to enter the Cell Cycle - Inducing T-cell Proliferation

What happens to naive T-cell once activated?

It stops, proliferates, and differentiates. Then it leaves the lymph as an Effector T-cell via lymphatic system

What is the function of Active Effector T-cells?

Kill Virus-infected target cells

What is different about L-selectin in the Effector T-cell?

L-selectin Adhesion molecules is no longer expressed in the Effecter (activated) T-cell It does not migrate back into lymphatics

What happens if there is Antigen Recognition but no Co-stimulatory signal?

Leads to functional INACTIVATION (Anergy) or Clonal Deletion of peripheral T-cells

What happens if there is only Co-stimulatory signal b/w APC & T-cell?

No effect

How is IL-2 receptor expressed in the resting T-cell?

Resting T-cells express only a Moderate-Affinity IL-2 Receptor (IL-2R beta & gamma chains only)

What happens to T-cell response after antigen is eliminated by effector cells?

T-cell response declines

What is the function of a mature dendritic cell?

TO present antigen to a naive T-cell via MHC molecule

What happens to DC once it captures bacterial antigen in the skin?

The DC migrates to the Dermis - From dermis it migrates to a draining lymphatic vessel.

Once in the lymph node, where does the DC settle?

The DC settles in the T-cell area - the Cortex

What causes T-cell Proliferation & Differentiation?

The binding of IL-2 with IL-2 Receptor

Where in the lymph nodes are dendritic cells found?

Throughout the cortex - in the T-cell area