Bio 328 Immunology

Tcell activation and differentiation

DN1

DN2 DN3 DN4 DP

SP

SP

Trabecular bloodvessel

Medulla

Cortex

Subcapsular sinus Capsule

Maturation of T cells in the Thymus.

Proliferation chain

rearrangementLymphoid precursor

Pro-T

Pre-T Post pre-T(pre-TCR)

Proliferation

chainrearrangement

Positiveselection

NegativeSelection

DoublePositive

SinglePositive

Precursor Pro-T pre-TPostPre-T

DoublePositive

SinglePositive

DN1 DN2 DN3 DN4 DP SP

C-kit + + - - - -CD44 + + - - - -CD25 - + + - - -

Pre-T - - + + - -CD3 - - + + + +CD4 - - - - + +CD8 - - - - + +

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 typeControl

miceMHC I

defMHC II

def

DN + + +

CD4+CD8+ + + +

CD4+ + + -

CD8+ + - +

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 selectiona. Affinity hypothesisb. Altered peptide hypothesis

(Marrack and Kappler).

2. DP to SP CD4 or CD8 cellsa. Instructive modelb. 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