bio 328 immunology tcell activation and differentiation
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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