Chapter 12 T lymphocytes

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Chapter 12T lymphocytes
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Introduction

• T cell maturation in the thymus
• T cell receptor and T cell accessory molecules
• T cell subsets

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Part I T cell maturation in the thymus

• Differentiation course of T cells
• Selection of T cells in thymus---- positive
  selection and negative selection
• TCR gene rearrangement during the maturation of T
  cells

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1. Differentiation course of T cells 1) pro T
cells CD3- TCR- CD4- CD8- TCR ß chain starts
to rearrange DN2) pre T cellsCD3
TCRpTaß CD4 CD8
3) immature T cells
DP CD3 TCR CD4 CD8 the
rearrangement of TCR a chain 4) mature T
cells CD3 TCR CD4 or CD3 TCR CD8
SP
TCR rearrangement
Thymus selection
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• Important events in the thymus
• TCR rearrangement ----Functional TCR
• Positive selection and Negative selection
• ----Mature T cell possess MHC restriction and
  self tolerance

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Pro-T cell
pT??
Pre-T cell
Immature T cell
Mature T cell
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2. Selection of T cells in thymus

• During the stage from DP (double positive) cells
  to SP (single positive) cells
• Depend on the interaction of TCR and Ag peptide
  and MHC molecules

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Positive selection

• If the TCRs of DP cells recognize and combine
  with Ag peptide---class I/II MHC molecules in an
  appropriate affinity, these DP cells will
  differentiate and develop continuously----SP
• If the TCRs of DP cells cant recognize Ag
  peptide---class I/II MHC molecules or recognize
  and combine with Ag peptide---class I/II MHC
  molecules in a high affinity, these DP cells will
  undergo apoptosis.
• Acquire self MHC restriction
• MHC molecules play important roles in positive
  selection
• MHC-I------CD8 expression
• MHC-II-----CD4 expression

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Negative seletion

• If the TCRs of SP Cells cant recognize self
  antigen peptide-class I/II MHC molecules or
  combine with self peptide-MHC molecules in a low
  affinity, these SP cells will differentiate and
  develop continuously.
• If the TCRs of SP Cells recognize and combine
  with self antigen peptide-class I/II MHC
  molecules in a high affinity, these SP cells will
  undergo apoptosis or become clonal anergy.
• Acquired self tolerance
• Self peptide play important roles in negative
  selection.

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3. TCR gene rearrangement during the maturation
of T cells

• (1) Gene structure of TCRaß
• achain (14 chromosome) V, J, C
• ßchain (7 chromosome) V, D, J, C

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(14 chromosome)
(7 chromosome)
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• (2) Gene structure of TCR?d
• ?chain (7 chromosome) V, J, C
• dchain (14 chromosome) V, D, J, C

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(7 chromosome)
(14 chromosome)
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(3) Characteristics of TCR gene rearrangement

• More J gene segment
• More N-nucleotides insert
• More CDR3 diversity

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Part II T cell receptor and T cell accessory
molecules

• Antigen receptor complex
• ------recognizing antigen
• Accessory membrane molecules
• ------Molecules related to the activation of T
• cells (co-receptors and co-stimulators)
• Other surface membrane molecules

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I. Antigen receptor complex of T cells
TCR and TCR complex
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1. TCR

• (1) Definition A kind of membrane molecule on T
  cells that can specially bind to the antigenic
  peptide-MHC molecule complex.
• (2) Types TCRaß
• TCR?d

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• (3) Structure of TCR
• Extracellular region
• V region V ? and V ?
• antigen binding site
• CDR1,CDR2,CDR3
• C region C? and C?
• Transmembrane region
• anchoring domain
• positive charged
• Cytoplasmic region

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Three dimensional structure of TCR
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2. TCR complex

• (1) Definition A group of membrane molecule on T
  cells that can specially bind to the antigen and
  pass an activation signal into cell, consisting
  of TCR (?? or ??) , CD3 (??,??,?? or ??,??, ??)

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• (2) CD3
• Consists of ??, ?? ,?? or ??,??, ??
• Important membrane molecule of T cells
• Contain ITAM in the cytoplasmic region
• Pass activatory signal into cells

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• ITAM (Immunoreceptor tyrosine-based activation
  motif)
• ITAM is composed of 15-19 amino acid residues,
  and contains YxxL/Vx7-11YxxL/V consensus
  sequence. When TCR binds antigen specifically,
  the tyrosine in the consensus sequence will be
  phosphorylated by the receptor associated
  tyrosine kinases in order to transduct activatory
  signal.

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• ITIM (Immunoreceptor tyrosine-based inhibition
  motif)
• ITIM contains I/VxYxxL consensus sequence and
  transducts inhibitory signal.

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II. Accessory membrane molecules on T cells

• 1. CD4 and CD8 co-receptor
• CD4----MHC-II (ß2)
• Receptor of HIV
• CD8----MHC-I (a3 )
• CD4 and CD8 also participate in signal
  transduction after TCR bind antigen specifically.

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T cell co-receptor molecules
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• 2. Co-stimulatory receptor CD28
• CD28 on silent or activated T cells binds to the
  B7 (CD80/CD86) on APC
• ----transduct an important co-stimulatory signal
  to T cells
• CTLA-4 (cytotoxic T lymphocyte antigen-4,CD152)
  on activated T cells binds to B7 on APC (The
  affinity is higher than that between CD28 and B7)
  
• ----transduct an inhibitory signal to T cells

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• 3. CD2 (LFA-2, Sheep red blood cell receptor )
• CD2 is expressed on 90 mature T cells, thymus
  cell and NK cell, but there is no expression on B
  cells.
• Its ligand is CD58 (LFA-3) expressed on APC, RBC
  of human or sheep.
• Functions
• ------Mediated the formation of E-rossete.
• ------Enhance the binding of TCR and antigenic
  peptide-MHC
• molecule complex.
• ------Participate in signal transduction of T
  cell activation.

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• 4. CD45 (leukocyte common antigen)
• Act as protein tyrosine phosphatase
• Express on mature and immature lymphocytes
• Possess various isoenzyme (One is CD45R)
• CD45RA------ Naïve T cell
• CD45RO------ Effector and Memory T cell

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• 5. CD40L (CD154)
• CD40L on T cell binds to CD40 on B cell or
  other APC
• ---Transduct a co-stimulatory signal to B cells
  
• ---Promote activation of B cells

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• 6. LFA-1
• ---Ligand ICAM-1,2,3
• ---Mediated adhesion between T cell and APC,
  vascular endothelial cells and extracelluar
  matrix

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III.Other surface membrane molecules

• 1. Mitogen receptor
• ---Related to lymphocyte transformation test
• PHA(?????), ConA(???? A)
• ---Activating T cell only
• PWM(????)
• ---Activating T and B cells
• 2. Cytokine receptor IL-1R, IL-2R
• 3. Class I and class II MHC molecules
• 4. L-selectin
• 5. CD44
• 6. VLA-4

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Part III T cell subsets

• According to activatory stage of T cells
• According to type of TCR
• According to expression of CD4 or CD8
• According to functions of T cell

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I. According to activatory stage of T cells

• Naïve T cell
• Effective T cell
• Memory T cell

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Comparison of three types of cells

• Naïve T cell Effective T
  cell Memory T cell
• stimulation of Ag no
  yes yes
• IL-2R (high avidity) no
  yes yes
• CD45 CD45RA
  CD45RO CD45RO
• Lymphocyte yes
  no yes
• recirculation

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II. According to type of TCR

• aß T cells
  ?dT cells
• TCR diversity many
  few
• Distribution
• Peripheral blood 60-70
  5-15
• Tissues lymph
  node,etc skin and mucosa
• Phenotype CD3CD2 100
  100
• CD4CD8- 60-65
  lt1
• CD4-CD8 30-35
  20-50
• CD4-CD8- lt5
  50
• Ag
  Peptide(8-17aa) lipid, HSP,etc
• MHC restriction yes
  no
• Functions Specific CMI
  nonspecific CMI

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• NKT cells
• ---- aß T cells existing in thymus, bone marrow,
  spleen and liver
• ----Express markers of NK cells (CD56 and NK1.1)
• ----Be lack of TCR diversity
• ----Recognize lipid antigen presented by class I
  MHC-like molecules (CD1d)

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III. According to expression of CD4 or CD8

• CD4 T cell CD8
  T cell
• Ag peptide exogenous endogenous
  
• 13-17aa
  8-10aa
• MHC restriction Class II Class
  I
• Major effective Th
  Tc
• cells

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IV. According to functions of T cell

• Th cell (Th1,Th2,Th17) ----CD4
• Tc cell or CTL----CD8
• Regulatory T cell (Treg) ----CD4CD25Foxp3

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What you should know by the end of this lecture

• Differentiation course of T cells in thymus
• Definition of TCR and TCR complex, ITAM and ITIM
• Major surface membrane molecules on T cell and
  their functions
• Main characteristics of subgroups of Tcells