Selection and Proposed Models of Lineage Commitment

TCR Affinity

If the TCR starts to bind MHC to strongly it might do so regardless of what antigen is being presented. This causes nonspecific activation of T cell responses and that in itself is bad that's how you get chronic inflammation. Look at the photo

Cells die by neglect and undergo apoptosis if they have a low binding afintiy

Cells die by apoptosis if they bind with a high affinity

Positive selection

Requires the association of a CD8 or CD4 co-receptor with the associated MHC molecule.

Negative Selection (AIRE)

• AIRE: leaky transcription factor expressed in mTECs to allow for the expression of self antigens in MHC

  • AIRE randomly transcribes self antigens encoded in your genome.

• If a TCR recognizes a self antigen during this stage of negative selection then it is deleted by apoptosis.

Positive selection: Instructive model

• If you engage the CD4 co-receptor in a positive way to MHC II, then you become a CD4

• If you engage the CD8, then you become a CD8

• All it takes is a positive signal to cause a differentiation of the double positive cell towards one way or the other

Positive selection: Stochastic model

• Random down-regulation of one of the co-receptors. Once this happens, if it's able to recognize the associated MHC, then it persist and if it is not it dies by apoptosis.

Positive selection: kinetic signaling model

• It takes a long time to decide which T-cell its going to be (CD4 or CD8)

• You have a fluid switch between CD4 and CD8 and it's a constant ying and yang till one wins out.

• So the T cell doesn't decide what it’s going to become until the end of the selection process.