1. Surface markers on T lymphocytes and their function

2. Subsets of T lymphocytes

3. Function of T lymphocytes

T lymphocytes

T cells are composed of a group of functionally different and heterogeneous lymphocytes. They are so called because they differentiate and mature in thymus.

Mature T cells emigrate thymus and reside ： in paracortical area of lymph node and around small arteries of spleen white pulp ： in peripheral lymphoid tissue.

T cells execute specific cellular immune response and play an important role in TD-Ag induced humoral immune response.

Part I T cell differentiation and development

Thymic microenviroment

Differentiation course of T cells

Selection of T cells in thymus---- positive selection and negative

selection

Hematopoiesis

1. Thymic microenvironment

2. T-cell Development pro T cells :CD3

- TCR- CD4

- CD8- (Double

Negative Cells, DN)

pre T cells:CD3+

TCRpTα:β CD4+ CD8

immature T cells CD3

+ TCR+ CD4+ CD8

+

mature T cells CD3

+ TCR+ CD4+

or CD3+ TCR+ CD8

+ (Single Poaitvie, SP)

(Double Positive C

ells, DP)

Stem cell

NaïveT-cell

CD44+

CD25-

CD4-8-

Bonemarrow Thymus Periphery

How T cells Encode the TCR Molecules?

T Cells

TCR

Germ-line organization of the mouse TCR α,β,γ and δ-chain gene segments

Germ-line Structure of TCR α,β,γ and δ-chain genes

-S-S-

V

C

V

C

TCR-

Gene Rearrangements Yield A Functional Gene

Encoding the αβ TCR or TCR

Rearrangement of TCR GenesIs to Produce Cell-surface

ReceptorsThat Are

Essential for T-cell

Development

Process Gene Rearrangement Cell

Junctional Diversity

Diversity of TCR

1016

Diversity of TCR Combinatorial diversity

Junctional diversity

Total: 1016

3.Differentiation of T cells in thymus

Changes in thymus：• TCR rearrangement ----functional TCR• Positive selection and negative selection T cells acquire MHC restriction and Self

tolerance

Positive selection

• DP cells whose TCRs recognize and combine with MHC molecules can differentiate and develop continuously----SP

• DP cells whose TCRs can’t recognize with MHC molecules or bind with high affinity go apoptosis

Positive Selection

• Results in MHC restriction• Mechanism:

– Immature thymocytes cluster with MHC molecules on the cortical cells of the thymus

• If TCR interacts with MHC protective signal results that prevents apoptosis.

• If TCR does not interact with MHC no protective signal and apoptosis occurs.

• Only reactive thymocytes survive.

Negative seletion

• cells whose TCRs can’t recognize with self antigen peptide develop and differentiate continuously

• SP cells whose TCRs recognize and combine with self antigen peptide tightly go apoptosis or become clonal anergy

• Acquired self tolerance

Negative Selection

Negative Selection

• Ensures self-tolerance• Weeds out High affinity thymocytes• Mechanism:

– APC’s bearing MHC’s interact with thymocytes• If avidity is too strong thymocyte undergoes

apoptosis.

• Only self-tolerant thymocytes survive.

Differentiation course of T cells 1) pro T cells

CD3- TCR- CD4

- CD8-

TCR β chain starts to rearrange DN

2) pre T cellsCD3

+ TCRpTα:β CD4+ CD8

+

3) immature T cells DP CD3

+ TCR+ CD4+ CD8

+ the rearrangement of TCR α chain

4) mature T cells CD3

+ TCR+ CD4+

or CD3+ TCR+ CD8

+ SP

TCR rearrangementTCR rearrangement

Thymus selectionThymus selection

Maturation of T cells in the thymus

PartII

Surface markers on T lymphocytes and their function

1.T cell receptor complex

T cell receptor complex------TCR-CD3 complex

TCR complex

Definition: A group of membrane molecules on T cells that can specially bind to the antigen and pass activation signal into T cells, consisting of TCR ( or ), CD3(,, )

TCR

CD3CD3

1. TCR

(1)Definition: A kind of membrane molecules on T cells that can specially bind to the antigenic peptide-MHC molecule complex

(2)Types ： αβTCR

γδTCR

(3) Structure of TCR(3) Structure of TCRExtracellular region:Extracellular region: V region: V V region: V and V and V antigen binding siteantigen binding siteC region: CC region: C and C and CTransmembrane region:Transmembrane region: anchoring domainanchoring domain positive charge positive charge Cytoplasmic region:Cytoplasmic region: cancan’’t transduce signalt transduce signal （ 3~12aa）

+ +

2 CD3 Consists of ,, Important membrane molecules of T cells Pass activation signal into T cells Contain ITAM in the cytoplasmic region

ITAM (Immunoreceptor tyrosine-based activation motif) :

• ITAM is a conserved motif composed of two copies of the sequence tyrosine-X-X-leucine found in the cytoplasmic tails of various membrane proteins that are involved in signal transduction.

• When these receptors bind their ligand, the tyrosine residues of the ITAMs will be phosphorylated by the receptor associated tyrosine kinases in order to transmit activation signal.

ITIM(Immunoreceptor tyrosine-based inhibition motif):

• ITIM contains I/VxYxxL(Isoleucine/ValinexTyrosinexx

Leucin) consensus sequence and transducts inhibitory signal.

2. T cell accessory molecules

Accessory molecules-----related to the activation

Part T cell accessory moleculesⅡ

1. CD4 and CD8: co-receptor CD4----class MHCⅡ Receptor of HIV CD8----class Ⅰ MHC

CD8 binds MHC class ICD4 binds MHC class II

Most mature T cells are either CD4+ or CD8+.CD8 T cells kill cells infected with intracellular pathogens or tumor cellswhile CD4 T cells regulate (activate or suppress) other immune cells’ function (e.g.B cells and mac).

To bind p56lck tyrosine-protein kinase ,involve in the signal transduction that leads to T cell activation and proliferation

LCK

2. Co-stimulatory receptor: CD28 CD28 on resting or activated T cells binds

to the B7(CD80/CD86) on APC Contain ITAM domainTransduct an important co-stimulatory signal

to T cells

activated T cell Antigen presenting cell

TCR

B7

MHC + peptide

CD28

ITAM

3. CTLA-4CTLA-4(cytotoxic T lymphocyte antigen-4,

CD152) on activated T cells binds to B7 on APC

Homologous to CD28Bind to B7 with high affinityContain ITIM domainTransmit an inhibitory signal to T cells

Part T cell accessory moleculesⅡ

T cell Antigen presenting cell

CTLA4 – a CD28 homologue thatbinds to B7 with higher affinity than CD28

TCR

B7

MHC + peptide

CD28

CTLA4ITIM

4. CD2(LFA-2, Sheep red blood cell receptor)

Expressed on 90% mature T cells( none on B cells) Its ligand is CD58(LFA-3) expressed on APC, RBC

of human or sheep Functions: ------Enhance the binding of TCR and antigenic peptide-MHC molecule complex ------Participate in signal transduction of T cell

activation

5. LFA-1(lymphocyte function antigen-1)• CD11a/CD18• Its ligand is ICAM-1(CD54),2,3• Mediated adhesion between T cell and APC or

target cell

6. VLA-4(very late antigen-4)• CD49d/CD29• Its ligand is VCAM-1,fibronectin,laminin• Mediated adhesion between T cell and APC or

target cell

Part T cell accessory moleculesⅡ

7. Mitogen receptor: ---Related to lymphocyte transformation testPHA, ConA ---Activating T cell onlyPWM ---Activating T and B cells

8. Cytokine receptor: IL-2R,IL-12R

PartⅡ T cell accessory molecules

The major surface molecules of CD4+ T cells involved in the activation of these cells (the receptors) and the molecules onAPCs (the ligands) recognized by the receptors are shown. CD8+ T cells usemost of the same molecules, except that the TCR recognizes peptide–classI MHC complexes, and the coreceptoris CD8, which recognizes class IMHC.

Subsets of T lymphocytes

1. According to activating stage of T cells

Naïve T cell

Activated T cell

Effective T cell

Memory T cell

Naïve T cell Memory T cellStimulation of Ag no yesIL-2R(high avidity) no yesCD45 CD45RA CD45RO MHC-Ⅱ molecule no yes ICAM no yes

2.To divide into αβT 、 γδT subsets according to TCR type

In peripheral blood ,αβT cells account for 95% while γδT cells range from 1% to 10% 。 The two subsets of T cells have different characteristics and functions. αβT cells are the main T cells participating in immune response.

TCR

Distribution

Phenotype

Antigen recognition

MHC restriction

Function

TCRαβT TCRγδT

high diversity

60-70 ％ , peripheral lymphoid

tissue

mature, CD2CD3CD4/CD8

8 － 17aa

classical MHC

Th 、 Tc

low diversity

5-15 ％ , mucosal epithelia

mature, mostly CD2CD3

simple polypeptide, HSP, lipid,

polysaccharide

MHC like molecules

Tc

TCRαβ T and TCRγδ T cells

TCRαβTCD4+ cells: TCR antigen recognition is MHC restrictive. Ⅱ

TCRαβTCD8+ cells:TCR antigen recognition is MHC I restrictive.

3. To divide to CD4+ T cells or CD8+ T cells according to whether T cells express CD4 or CD8

Th cell (Th1,Th2,Th17) ----CD4+

Tc cell or CTL----CD8+

Regulatory T cell (Treg) ----CD4+CD25+Foxp3

4 Functional subsets ： Th 、 Tc 、 Tr

Master the types and structure of TCRMaster T subset categories and the biological features of different subsetsMaster the developmental process of T cellsFamiliarize the main membrane molecules on T cell surface and their functionUnderstand the similarity and differnce between TCRγδT cells and TCRαβT cells