CHAPTER 9 BIOLOGY OF THE T LYMPHOCYTE

CHAPTER 9 BIOLOGY OF THE T LYMPHOCYTE Coico, R., Sunshine, G., (2009) Immunology : a short course, 6 th Ed., Wiley-Blackwell 1

CHAPTER 9 : Biology of The T Lymphocytes 1. 2. 3. 4. 5. 6. 7. Introduction Nature of the Antigen-Specific T Cell Receptor T Cell Genetics T Cell Differentiation in the Thymus Thymic Selection Single Positive T Cells Differentiation of Other Sets of Cells in Thymus 2

CONTENTS 1. Introduction 2. Nature of the Antigen-Specific T cell Receptor 2-1 Molecules that Interact with Antigen 2-2 Coreceptor Molecules 2-3 The T Cell Receptor Complex 2-4 Other Important Molecules Expressed on the T Cell Surface 2-5 γδ T cells 3. T Cell Genetics 3-1. Genes Coding for T Cell Receptors 3-2. T cell Receptor Gene Rearrangement 3-3. Generation of T Cell Receptor Diversity 4. T Cell Differentiation in the Thymus 4-1. Thymocytes Interact with Thymic Nonlymphoide Cells 4-2. Development of αβ T cells and γδ T cells 4-3. Thymocytes Maturation & Selection 5. Thymic Selection 5-1. Positive Selection 5-2. Negatie Selection 5-3. Role of AIRE Gene Product in Negative Selection 6. Single Positive T cells 7. Differentation of Other Sets of Cells in Thymus 3

1. Introduction 1. Location of the antigen - B cell & Ab ; Outside of the cell - T cells ; Inside of the cell (TcR cannot access to the antigens directly) 2. T Cell Receptor (TcR) Diversity - 10 15 ~10 18 different possible structures - The organization of the genes that TcR & BcR are strikingly similar 3. Differentiation of T cells & T cell education 4. Kinds of T Cell Receptors : - αβ TcR ; MHC restriction, (Th, CTL) - γδ TcR ; no MHC restriction 4

2. Nature of the Antigen-Specific T Cell Receptor CDRs on TcR 5

Differences between TcR & BcR Valence & conformation Antigen Secretion of the Receptor affinity maturation (somatic hypermutation) BcR bivalent & flexible at hinge region linear and conformational Yes Yes TcR mono-valent & rigid conformation only linear peptide associated with MHC molecules No No 6

[2-1] Molecules That Interact with Antigen Triple complex of MHC:pep:TcR 7

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[2-2] Coreceptor Molecules α3 β2 Fig. 8.3. The TcR coreceptors and their interaction with MHC molecules 9

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Figure 1. The life cycle of HIV presents several targets for inhibition. S. Nawale et al (2010) Int.J. ChemTech Res. 2(2), 1180-85. 12

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[2-3] The T Cell Receptor Complex ITAM ITAM : Immunoreceptor tyrosine-based activation motif 14

[2-4] Other Important Molecules Expressed on the T cell Surface 1. Coreceptor Molecules : does not bind antigen but enhances T cell activation - CD4(1 chain) or CD8(2 chains) : CD4 + T cell and CD8 + T cell CD4 : MHC class II β 2 (professional APC and thymic epithlial cells) CD8 : MHC class I α 3 (all nucleated cells) 2. Costimulatory Ligands (for second signals) T cell APC Function CD28 B7-1(CD80), B7-2(CD86) IL-2 production CD40L (CD154) CD40 (professional APCs) CTLA4 (CD152) B7 Enhance CD28-B7 interaction For B cells isotype switching Negative signal to activated T cells (Terminate T cell activation) 15

[2-4] Other Important Molecules Expressed on the T cell Surface 3. Adhesion Molecules T cell APC Function CD2 LFA-3 (CD58) Adhesion LFA-1 (CD11aCD18) VLA-4 (CD49dCD29) 4. Homing Molecules ICAM-1 (CD54) VCAM-1 Early, naïve T cell Function Addressins at HEV of CD62L (L-selectin), α4β7 CCR7 To enter LNs peripheral Node mucosal Node Chemokine receptor http://www.youtube.com/watch?v=_oi0jvn4tti&feature=youtube_gdata_player 27 ; phagocytosis, 31 ; chemokine attraction 39 ; B/T 16

Fig. 9.4. Important molecules expressed at T-cell surface. Hatched bars indicate expression induced on activated cell.

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[2-5] γδ T cells γδ T Cell not restricted by MHC - T cell receptor의 alternative form; αβ TcR 대신 γδ TcR - Found at mucosal epithelial sites (skin, gut, lung etc) - 기능, 항원의종류도전혀다름 mycobacteria, phospholipids, phosphoantigens, heat-shock proteins [2-6] NKT cells αβ T Cell not restricted by MHC - Bear NK cell surface marker (NKT란명칭의유래 ) - Do not recognize peptides displayed by APC recognize lipid antigens on CD1 molecule. - secretes cytokines 21

3. T Cell Genetics cock hen chicken 가족사진촬영 Scary time to be a Chicken

[3-1] GENES CODING FOR T CELL RECEPTORS Ch 7 Ch 14 Ch 7 23

[3-2] T Cell Receptor Gene Rearrangement 24

Ig gene expression 과특이하게다른점 : 1. No isotype switching : no changes in functions 2. No somatic mutation : no affinity maturations 3. TcR β chain has V-D-J-C and also V-J-C rearrangememt 25

[3-3] Generation of T Cell Receptor Diversity 26

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4. T Cell Differentiation in the Thymus 1. Migration and proliferation: Bone marrow (precursor) Thymus (cortex medulla) Periphery 2. Differentiation (in thymus; immature T cell) TcR:CD3 accessory molecules (include CD4, CD8) 3. Selection (in thymus; mature T cell) Thymic Education Positive selection : became germ-line encoded self-mhc restricted T cell Negative selection : eliminates auto-reactive clones; the rests became self-tolerant and foreign Ag specific mature T cell 28

T CELL MIGRATION & DIFFERENTIATION 흉선은사춘기이후퇴화된다 - DiGeorge syndrom : Normal Ig, 세포성면역부전 반복감염, 귀, 코, 입기형유발 deletion of chromosome 22q11 absence of parathyroid gland no or very few T cells congenital thymic aplasia ( 선천성흉선무형성증 ) - Nude mouse(thymus not developed & lack of hair), SCID mouse 29

[4-1] Thymocytes Interact with Thymic Nonlymphoid Cells 30

Thymic epithelial cells express both MHC class I and II molecules Also produce IL-7 31

[4-2] Development of αβ T cells and γδ T cells Key stages in development of and T cells in the thymus. -TCR gene expression - Coreceptors CD4 and CD8. -The single line ( ) at the surface represents CD3 +. 32

[4-3] Thymocytes Maturation & Selection 95% of the T cells dies in the thymus during T cell education! 33

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5. Thymic Selection General features ⑴ TcR must be expressed before selection ⑵ Random TcR expression give total repertoires for MHC and any antigen ⑶ Positive selection (self MHC recognition survive) ⑷ Negative selection (removal of self antigen recognition) * clonal deletion ; elimination clonal anergy ; inactivation (cf. no energy) ⑸ Double positive T cell 이 Positive & negative Selection 을거친후에야 Single Positive T cell 이된다. 35

Development of the self MHC-restricted T cell repertoire (1) The role of MHC, CD4 and CD8 in positive selection 1 Occurs during T cell passage through thymus by contacting with nurse cells. (T cell 의 maturation 과정중, 자신의 MHC 분자가아니라흉선상피세포의 MHC 분자에의한결합이며, 따라서 Thymocytes whose TcR has no affinity for self MHC will die) 2 Positive selection may be a result of the activation of thymocytes after the binding of their TcRs with self MHC molecules. without this stimulation, thymocyte will die (programmed cell death) 3 CD4 molecules recognize MHC classⅠ CD8 molecules recognize MHC classⅡ 4 Peptides also play a role in positive selection (TAP-1, TAP-2, 2C-pep) [5-1] Positive Selection (2) Mechanisms of Positive Selection in the Thymus Right combination of TcR may generate some signal to rescue of a thymocytes from programmed cell death. 36

[5-2] Negative Selection (1) Development of self-tolerance - deletion or inactivation of self-reactive clones of T cells during their maturation in the thymus ; T cell tolerance to self. - Bone marrow derived cells within thymus, such as dendritic cells, and MΦ can present self antigens to and cause the deletion of self antigen reactive T cell clones. (2) Mechanism of Negative Selection in the thymus. - Clonal deletion in the thymus : apoptosis [cell shrinkage, DNA fragmentation into nucleosome and nuclear fragmentation] - This apoptotic cell death is turned on by TcR-generated signals (activation-induced cell death). * Certain Vβ gene segment(vβ17a) in a TcR β chain 에결합하는 superantigen (peptide + I-E) 이있어서이러한 mouse 의 cortex 에는 TcR with Vβ17a 가존재하나 medulla 및 periphral organ 에는 delete 되어나타나지않음. [CD4 와 Vβ17a+TcR 및 I-E classii MHC molecule 들에의해 Vβ17a 가 deletion 된다.] 37

[5-3] Negative Selection-Role of AIRE gene Product How do we develop self-tolerance to molecules normally found outside the thymus? Certain Vβ gene segment(vβ17a) in a TcR β chain 에결합하는 superantigen (peptide + I-E) 이있어서이러한 mouse 의 cortex 에는 TcR with Vβ17a 가존재하나 medulla 및 peripheral organ 에는 delete 되어나타나지않음. CD4 와 Vβ17a+TcR 및 I-E classii MHC molecule 들에의해 Vβ17a 가 deletion 된다. Insulin(pancrease), thyroglobulin(thyroid), MBP(CNS) are expressed by thymic medullary epithelial cells. Autoimmune Regulator (AIRE) gene product encodes a transcription factor regulator allowing peripheral tissue antigens to be expressed in the thymus. 38

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These topics are unclear and the subject of intense research activities! 40

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FIGURE 9.7. Positive and negative thymic selection: positive selection, showing interaction of TCR + CD4 + CD8 + double-positive cell with cortical epithelial cells; negative selection, showing double-positive cell interacting with thymic dendritic cell.

6. Single Positive T Cells 1) Single Positive T cells ; Negative selection in thymus down regulated the expression of CD4 or CD8 resulting in CD4 + or CD8 + T cells. Leave the Thymus via blood stream to secondary lymphoid organ utilizing adhesion molecules and chemokin receptors. Naïve T cells may live for a long time(up to years) in a resting state. Mature T cells in ther periphery that have not encountered antigen need signals (including IL-7) to keep them alive. 2) Characteristics of αβ T Cells Emerging from Thymus ; (a) Self-MHC restricted (b) Self-tolerant 3) By antigen activation, T cells become effector T cell or memory T cell 43

7. Differentiation of Other Sets of Cells in Thymus Other sets of cells developed in the thymus and found at outside of the thymus (1) NK Cell - double negative cell 단계에서분리되는 cell line 으로 do not express TcR - part of the innate immune defenses against virus-infected and tumor cells (2) NK like cell expressing TcR - respond to glycolipid not by MHC but by CD1d - have features of both the innate and adaptive defenses. (3) Treg Cells - a subset of CD4+ T ells (~10% of peripheral helper T cells) - characteristically express CD25 and transcription factor Foxp3. - recognize combination of self MHC and self peptide, but have survived negative selection in the thymus. - Inhibitory response to self and foreign antigens to maintain and regulate self tolerance. 44

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