S86 T-cell receptor and T-cell activation

What happen to T-cell activation if we have a defect in MHC class 1?

Then we only have CD4+ T-cells because only MHC class 2 is present

Expected outcome for RAG deficiency with regards to B cells, T-cells, and NK cells?

- lack of T-cells and B-cells - normal NK-cells because RAG is important for rearrangement and only T-cells and B-cells do rearrangement

Jak3 Expected outcome for Jak3 deficiency with regards to B cells, T-cells, and NK cells?

- lack of T-cells and NK-cells - normal number of B- cells, but reduced functions (no class switching)

Briefly explain T-cell development

1. Starts off as immature T-cells (double negative). 2. Rearrangement occurs to generate 2 types of T-cells (αβ or γδ double positive cells) 3. αβ double positive cells are more dominant!! They undergo positive selection and negative selection to delete self-reactive cells

Describe the gene rearrangement of T-cell

After gene arrangement, double negative T-cells become double positive T-cells: 1. Beta-chain rearrangement: step-wise V(D)J receptor rearrangement (requires Rag and TdT) 2. Must signal through a pre-TCR to stop beta chain rearrangement and rearrange the alpha chain. Failure to do so leads to T cell death

Expected outcome for IL-2 gamma chain deficiency with regards to B cells, T-cells, and NK cells?

Because it is shared among many receptors including IL-7 and IL-15, deficiency will lead to: - a lack of T-cells and NK cells. - normal number of B-cells but reduced function because we need T-helper cells for class-switching

Describe what happens when CD28 binds to B7(CD80)

CD28 binding induces upregulation of cytokine IL-2, which induces T cells to further proliferate and avoid apoptosis

Role of CD3 molecule in T-cell activation

CD3 is associated with TCR and contain signaling components necessary during T-cell activation

How do CD4 T-cells promote CD8 T-cells?

CD4+ promotes memory CD8+ T-cells

SCID (severe combined immunodeficiency)

Can be divided into four categories: 1. impaired lymphocyte survival 2. impaired cytokine signaling 3. impaired T cell signaling 4. impaired VDJ recombination Study Dr. Cortes' Excel Sheet

Where do positive and negative selections occur?

Cortex of thymus

Describe negative selection

Eliminate T-cells that failed to or too strongly recognize antigen-MHC complex

IL-2 gamma chain

IL-2 gamma chain is shared among many receptors including IL-7 and IL-15

IL-7R Expected outcome for IL-7R deficiency with regards to B cells, T-cells, and NK cells?

IL-7R is important for T-cell development and homeostasis. Deficiency in IL-7R will lead to: - a lack of T-cells - normal number of B-cells but reduced function - normal NK cells (because IL-15 is normal)

IL-15

Important for NK cells developments

IL-7

Important for T-cell development

How does T-cell development coordinate with stages of development in the thymus?

Interaction with stromal cells (thymic epithelial cells) leads double negative T-cells to move through the stages of development

What cells are antigen-presenting cells?

Macrophages Dendritic cells B-cells

After positive selection and negative selection, what are T-cells called at this stage?

Naive CD4+ or naive CD8+

What happen if we don't have negative selection?

Negative selection is critical for tolerance, and lack of negative selection leads to autoimmunity (APECD is an example of this)

Jak3

Required for both T-cell and NK cells development, not B-cells (but required for class switching)

DiGeorge's Syndrome

Study Dr. Cortes' Excel Sheet

What is TCR?

T-cell receptor that recognizes antigen-MHC complex

Describe positive selection

TCR of double positive T-cells interact with MHC I or II of thymic epithelial cells and differentiate into CD4+ or CD8+. Cells have to react to self strongly enough to be selected (positive), but weak enough to avoid negative selection.

What happen to T-cell activation if we have a defect in MHC class 2?

Then we only have CD8+ T-cells because only MHC class 1 is present

Role of thymic epithelial cells

They are important throughout T-cell development. Without these cells, T-cells do not move from one stage of development to another to become naive T-cells. There will also be no positive selection

Role of dendritic cells in T-cell activation

They are the main antigen-presenting cells that activate T-cells during an infection

What happens to T-cells that do not recognize self-antigen?

They undergo negative selection and die

Now that we have naive T-cells, how are T-cells activated to become effector CD4+ and CD8+?

Through 3 signals: 1. Activation: between TCR and MHC 2. Survival: CD28 (on TCR) binds to ligand B7 (CD80) on antigen-presenting cells to induce T-cells to further proliferate and avoid apoptosis 3. Differentiation: cytokines induce T-cells to differentiate further. In the case of CD4+ T-cells, interleukins push them into Th1, Th2, Th17, Treg (S87 lecture)

Role of CD4 and CD8 co-receptors in T-cell activation

When TCR of either CD4+ T-cells or CD8+ T-cells binds to antigen on the MHC complex, CD4 and CD8 co-receptors bind to the MHC molecule too to stabilize the whole structure (by strengthen the binding, facilitate signal transduction, and lower the threshold for activation)

When and where do naive CD4+ or naive CD8+ become mature T-cells?

When they are activated by MHC presented by macrophages or dendritic cells (T-cell activation) Paracortex of the secondary lymphoid organs

How would a defect in CD4 co-receptor affect positive selection?

Would need a lot more TCR and MHC to induce activation

How would a defect in CD8 co-receptor affect positive selection?

Would need a lot more TCR and MHC to induce activation

Describe immunological synapse and its importance in T cell activation

a stable TCR-MHC junction to reinforces TCR signal (like synapse in neurons)

What happen if signaling happens in the absence of signal 2?

anergy (absence of the normal immune response) or death

Describe how T-cell development and B-cell development differ

• T cells require IL-7 for development • There are two lineages that can develop, aβ and γδ T cells, but most cells become aβ • Strength and length of signal determines whether or not cells become CD4 or CD8+ T cells (DP stage)