T cells I. T cell maturation in the thymus II T cells I. T cell maturation in the thymus II. T cell receptor and T cell accessory molecules III. T cell subsets

I. T cell maturation in the thymus 1. Process 2. Events

1.Process 1) pro T cells CD3- TCR- CD4- CD8- TCR β chain starts to rearrange DN 2) pre T cells CD3+ 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 b Pre-Ta Vpre-T？ g e e d 信号转导 Lck，ZAP-70，Syk Pre-TCR

2.events 1) rearrangement of TCR gene 2) positive selection and negative selection

Rearrangement of TCR gene (1) germline gene structure of TCR (2) rearrangement of TCR genes (3) characteristics of the rearrangement of TCR genes (4) The mechanism of diversity of TCR

(1) Germ-line Gene structure of TCRαβ αchain(14 chromosome): V, J, C βchain(7 chromosome): V, D, J, C

(2) Gene rearrangement of TCRαβ αchain: VJ VJ-C VJC DNA RNA mRNA β chain: DJ VDJ VDJ-C VDJC DNA RNA mRNA

(3) Characteristics of the rearrangment of TCR genes allelic exclusion

(4) The mechanism of diversity of TCR 1) (4) The mechanism of diversity of TCR 1). Mutiple germline gene segments 2). Combinatorial V(D)J joining 3). Junctional flexibility imprecise joining and N-nucleotides addition 4). combinatorial assocination of α andβ chain

Comparison of BCR and TCR functional genes NO. of chain Chromosome V D J C ----------------------------------------------------------------------- BCR H 14 48 23 6 10  2 40 0 5 1  22 30 0 4 4 TCR  14 50-100 0 100 1  7 20 2 14 2  7 7 0 4 4  14 5 2 6 1 -------------------------------------------------------------------------

2) positive selection and negative selection MHC restriction self tolerance

胸腺小叶 被膜 被膜下区 皮质 髓质 骨髓 CD3‾CD4‾/LOW CD8‾ TCR‾ CD3‾CD4+ CD8‾ TCR‾ CD3LOWCD4‾CD8+ TCRabLOW CD3+ CD4+ CD8+ TCRab+ CD3+ CD4+ CD8‾ TCRab+ CD3+ CD4‾ CD8+ TCRab+ CD3+ CD4+ TCRab+ CD3+ CD8+ TCRab+ CD3+ CD4+ CD8+ TCRgd+ CD3+ CD4+ CD8‾ TCRgd+ CD3+ CD4‾ CD8+ TCRgd+ CD3+ CD4‾ CD8‾ TCRgd+ CD3+ TCRgd+ CD3‾CD4‾/LOW CD8‾ TCR‾ 被膜 被膜下区 皮质 骨髓 髓质 胸腺小叶

Positive selection DP cells whose TCR can recognize and combine with peptide-MHC molecule complexes expressed on the cortical epithelial cells in an appropriate affinity differentiate continuously to become SP cells. DP cells whose TCR can’t combine with pepetide-MHC molecule complexes or can combine with them in a high affinity go apoptosis Get MHC restriction MHC molecules play important role in positive selection: MHC-I-------CD8+ expression MHC-II------CD4+ expression

Negative seletion SP cells whose TCR can’t combine with peptide-MHC complexes expressed on the DC or macrophages tightly develop and differentiate continuously SP cells whose TCR recognize and combine with self antigen peptide –MHC complexes tightly go apoptosis Acquired the self tolerance

II. T cell receptor and T cell accessory molecules T cell receptor complex T cell accessory molecules

TCR complex, Co –receptor, Co-stimulator receptor, immunological synapse

1.TCR cell receptor complex: a group of membrane molecules on T cells that can specially bind to the antigen and pass an activation signal into the cells, consisting of TCR (,) and CD3(, ,  or η)

TCR: a kind of membrane molecule on T cells that can specially bind to the antigen (Recognize specifically with Ag-MHC complex) αβTCR External segment ------V region, C region Transmembrane segment Cytoplasmic segment γδTCR

CD3: consisting of ,,  or η contain ITAMs, pass signal into cells ITAM: immune receptor tyrosine-based activation motif-----transduce activation signals from TCR

α：阿尔法 Alpha β：贝塔 Beta γ：伽玛 Gamma δ：德尔塔 Delte ε：艾普西龙 Epsilon ζ ：捷塔 Zeta η：依塔 Eta

2. T cell accessory molecules (1) co-receptors ---CD4 and CD8 (2)costimulatory molecule receptors ----CD28, CTLA-4 (3) CD40L (4) CD45 (5) CD2 (6) mitogen receptor (7) Cytokine receptor

co-receptors CD4 and CD8 CD4—MHC-II （β2） CD8----MHC-I (α3 ) Assist to recognize antigens Promote the activation of T cells

Promote the signal transduction

CD28 bind to the B7(CD80/CD86) on APC (antigen-presenting cell) ----transduce a co-stimulatory signal to T cell CTLA4 (cytotoxic T lymphocyte antigen-4, CD152) bind to B7 on APC ---transduce a inhibitory signal to T cell ITIM

CD40L CD40L --- CD40 on B cell CD45 ---transduce a co-stimulatory signal to B cells CD45 A cell surface glycoprotein with a cytoplasmic tyrosine phosphatase domain, is believed to play a role in T cell activation.

CD2(erythrocyte receptor) ----E-rosette test CD2---IFA-3(CD58): promote the cells contact each other. LFA-1 lymphocyte function associate antigen –1: its ligand is ICAM (intercellular adhesion molecule).

Mitogen receptor PHA(phytohemagglutinin), ConA(concanavalin A) ------activating T cell only PWM(pokeweed mitogen) -----activating T and B cells lymphocyte transformation test Cytokine receptor IL-1R, IL-2R etc.

III. Subsets of T cells according to activation naive T cells, effective T cells and memory T cells according to TCR  T and  T according to CD4/CD8 CD8+ Tcells, CD4+ Tcells according to fuctions Th, Tc/CTL and Treg

naive T cell and memory T cell                       naive T cell-----activated T cell---------- effective T cell and memory T cell naïve T cell memory T cell stimulation of Ag no yes IL-2R no yes CD45 CD45RA CD45RO MHC-II no yes ICAM no yes Ag

Classification according to TCR  T cells:  T cells:

Comparison of  T and  T ----------------------------------------------------------------------------- Characteristics  T cells  T cells ------------------------------------------------------------------------------- TCR more diversity less diversity peripherial blood 85-95% 5-15% tissue peripherial lymphoid mucosa epithelia tissue ------------------------------------------------------------------------------

Classification according to CD4/CD8 CD3+CD4+CD8-T --CD4+T: MHC-II CD3+CD4-CD8+T--CD8+T: MHC-I

Classification according to T cell function 1.Th (help T cells): (Th1, Th2)----CD4+ 2.Tc ( CTL): ----CD8+ 3. Treg: ----CD4+, CD25+ , Foxp3+

T cells 1. stages of T cell maturation in the thymus 2 T cells 1. stages of T cell maturation in the thymus 2. mechanisms of TCR diversity 3. positive selection and negative selection 4. TCR complex and some T cell accessory molecules 3. T cell subsets