Bio 328 Immunology Tcell activation and differentiation

DN1 DN2 DN3DN4 DP SP Trabecular bloodvessel Medulla Cortex Subcapsular sinusCapsule Maturation of  T cells in the Thymus. Proliferation  chain rearrangement Lymphoid precursor Pro-T Pre-TPost pre-T (pre-TCR) Proliferation  chain rearrangement Positive selection Negative Selection Double Positive Single Positive

PrecursorPro-Tpre-T Post Pre-T Double Positive Single Positive DN1DN2DN3DN4DPSP C-kit CD CD Pre-T  CD CD CD  chain  chain

“Thus, the MHC haplotype of the thymus in which the thymocytes develop determines the MHC restriction of the T cells.” Zinkernagel RM et al.

Evidence for Positive Selection: Ada Kruisbeek et al.

Knock-out mice Cell type Control mice MHC I def MHC II def DN +++ CD4 + CD CD CD Effect of class I or ll MHC deficiency on thymocyte populations.

Transfection of re-arranged TCR  and  chain genes.

Harald von Boehmer et al. (1989)

Negative Selection

Absence of Positive selection

Evidence for negative selection (Marrack & Kappler)

Evidence for negative selection: Effect of Staphylococcys enterotoxin.

Mls superantigens (mouse mammary tumor virus) AKR mouse are Mls1-positive

Evidence for negative selection: (Minor-lymphocyte stimulating antigens)

Central issues in thymic selection. 1. Positive and negative selection a.Affinity hypothesis b.Altered peptide hypothesis (Marrack and Kappler). 2. DP to SP CD4 or CD8 cells a.Instructive model b.Stochastic model

Affinity Model.

Altered Peptide Model (Philippa Marrack and John Kappler)

IPEX = Foxp3 deficiency = Immunodysregulation Poly- Endocrinopathy Enteropathy X-linked

Canale-Smith syndrome

The End