Lecture 9: T cell development 2

Cortical Thymic Epithelial Cells = cTEC

****DP cells express both CD4 and CD8, but mature T cells express one or the other

• WHAT is this decision is called

Lineage commitment

*****Different TRANSCRIPTION FACTORS mediate CD4 or CD8 differentiation

• What is the transcription factor that mediates CD4 vs. CD8 differentiation?

CD4 = thPOK

• inhibit CD8 + Runx3 + promote CD4

CD8 = Runx3

• inhibit CD4 + ThPOK + promote CD8

******What is the Kinetic signalling model

most accurate model proposed to explain How does a DP cell become a single positive cell

********Explain the Kinetic signaling Module mechanism. How does it work?

At the start (far left), immature T cells are DP. They interact with a cTEC (cortical thymic epithelial cell) presenting self MHC + peptide during positive selection to test their T-cell receptor (TCR).

1. during positive selection DP cells DOWN REGULATE CD8 (universal down regulation) = becomes CD4+8low

2. From this stage CD4+8low, the cell's fate splits depending on whether it can maintain its TCR connection:

• If the cell can still receive continuous TCR signaling, it means it engages normally with MHC II and it will develop into a CD4+ T cell

  • activate transcription factor ThPOK

• If the cell is impaired in its ability to interact, it will receive a weaker TCR signaling (disrupted), meaning it engages with MHC I, it will develop into a CD8+ T cell

  • activates a different transcription factor (Runx3

Before this choice even starts, the T cell has already generated its unique T-cell receptor (TCR). It doesn't know what its TCR matches yet, but the TCR is physically shaped to fit either MHC I or MHC II. the continuous vs. weak signal only confirms which CD T cell it should become/ which it is more suited to be

*****A secondary NEGATIVE SELECTION occurs to SP T cells

• WHERE does this secondary negative selection occur?

• Which cells mediate this selection?

Occurs in MEDULLA

• mediated by mTECs (medullary thymic epithelial cells) and some dendritic cell

******What is special about mTECs?

• What does this unusual ability allow mTEC to do interms of educating/selecting T cells?

mTECs have the unusual ability to express proteins that are usually tissue restricted

• i.e. it can express insulin which is normally

  expressed by B cells in the islets

  of the pancreas

Allows T cells to be educated against tissue-specific Ags before they leave the thymus

*****What does the expression of tissue-restricted Ags require?

An epigenetic regulator:

AIRE (AutoImmune Regulator)

*****What is APECED

• What causes it?

• What is the phenotype

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy: An immunodeficiency that manifests as autoimmunity

• CAUSED by: mutations in AIRE gene develop = T cells reactive to tissue-restricted self Ags are not deleted in the thymus

Results in different autoimmune phenotypes in different patients

• endocrine autoimmunity: hypoadrenalism, hypoparathyroidism, hypothyroidism

• type I diabetes

• autoimmunity in other organs

****Where does FINAL T cell MATURATION occur?

OUTSIDE the thymus

• T cell development takes 1-3 weeks

  • like B cells, T cells that recently

  emerge from the thymus are

  not fully mature

******What are RTEs?

Recent thymic emigrants RTEs

• T cells that recently emerge from the thymus and are not fully mature

• some similarities with transitional B cells

• do not proliferate or become activated in response to Ag to the same extent as more mature T cells

****CHeck last few slides of Lecture 9 for some review