Lineage Commitment and Activation

Activation of a Naïve T-cell

• TCR Signaling

  • Interaction of a mature T-cell receptor w/ antigen in the context of MHC.

    • Dependent on the expression of a co-receptor

• 2nd signal: co-stimulatory interaction

• third signal: cytokine signaling

• Cytokines signal through cytokine receptors

A signal is

Only as strong as the receptor that is detecting it

cSMAC

• Central immune synapse

• Central signal: signal 1

• TCR/CD3

• Co-receptors CD4 or CD8

• Co-stim receptors (CD28)

pSMAC

• Peripheral immune synapse

• Peripheral signal: signal 2

• Co-stim molecules.

• There are some adhesion molecules which make the cells stick together.

Immune synapse

Space which the primary signal, the co-receptors & co-stim signal are all residing in the cell membrane.

Signal 1 aka primary signal

• TLR signaling complex which involves a functional and mature TCR along with CD3. CD3 needed to provide the ITAMs. Bringing the ITAMs into proximity fires the signal downstream of the signaling cascade.

• By the time you leave the thymus you have the ability to recognize antigen with a functional TCR (primary signal).

  • A naive T-cell

Signal 2

• Recognized antigen & received a co-stim signal

• Co-stim signal

  • is given by cells that are immunologically active.

    • Immunologically active: APC recognition through PRR, engulf antigen, puts on MHC

  • The co-stim receptor CD80/86 is part of APC activation

  • CD80/86

    • Ligands for CD28 co-stim receptor on T cell

• Once the T cell expresses CD28 in the context of antigen then it becomes an activated T cell.

• An activated CD4+

  • kicks out cytokines

• An activated CD8+

  • It is now licensed to go out and make granules & start killing infected host cells

Signal 3

• Cytokines signal back to the T-cell & they can drive the differentiation and the immune response that’s downstream of that activated T -cell

• The most important signal 3 for a T-cell is IL-2.

• IL-2 is a cytokine that causes clonal expansion of an activated T-cell

• Once a naive T-cell becomes activated it up-regulates IL-2 & the high-affinity IL-2 receptor and begins proliferating.

  • Proliferating: the cell is being kicked into mitosis so it can divide

• Clonal proliferation creates daughter cells that have the same rearranged TCR & co-stim up-regulated.

• Most daughter cells will become effector T-cells, while some become memory T-cells.

  • Effector T-cells: cytokine factories that drive the immune response and lead to pathogen elimination

• There are multiple models of memory T-cell differentiation.

• Paracrine: providing cytokines that are signaling to cells in close proximity

• Autocrine:

  • is when a cell makes cytokines and then it signals back on itself.

  • In the picture the T-cell is making IL-2 and then IL-2 signals back through the IL-2 receptor on the cell that made the IL-2.

Signal 3 continued

• APC can make IL-2 in the presence of primary and co-stim signals. This APC could be making signal 2 to feed the T- cell to get it to start proliferating. This is called paracrine signal.

• Paracrine usually within the same physical location in the tissue.

• Auto: self

Polarizing & effector cytokines & paracrine signaling

• The decision of a T cell to become one subset or another comes in the form of a polarizing cytokine signal.

• Once you become one of these T cell subsets you create more effector cytokines.

• These effector cytokines can signal back to create more of themselves. This signal is called a paracrine signal (refer to picture)

  • These effector cytokines can circle back to create more of its lineage, and you get amplification of the T cell signal

Steps to T-cell Activation

1. Activation signal

2. Co-stimulatory signal

3. Subset differentiation signal

4. Functional T-cell subset

   • Differentiated T-cell subset

   • Within the subsets you can either be an effector or memory T- cell.