T Cells and T Cell Receptors: Development and Immune Responses

T Cells and T Cell Receptors

Learning Objectives

On completion of this session you should be able to

1. Describe the structure of the T cell receptors (TCRs).
2. Explain how TCRs recognise and bind to peptide-MHC complexes.
3. Comprehend TCR gene rearrangement and diversity.

Introduction to T Cells

1. Provide cell mediated immunity of adaptive response
2. Different populations of effector T cells: cytotoxic (CD 8+ Tc) helper (CD 4+ T-1, TH2, TFH)
3. Four principal effector functions: induce cell death - T. activate macrophages/inflammation - T_1 anti-parasitic response - T_2 mediate B cell activation - TEH
4. Activity is mediated through interactions between cell surface proteins on T cells (TCR) and target cells (MHC - peptide)

T Cell Receptor Structure

1. Protein complex of TCR and associated proteins
2. TCR comprises 2 polypeptide chains - a:3 or y:8
3. a:B TCRs are most common
4. Associated CD3 proteins provide signalling function
5. Co-receptors are required for ligand recognition - CD4 or CD8
6. Two main populations of T cell exist based on co-receptor expression -> CD 4+ and CD 8+

TCR Recognition and Signaling

T cell Receptor TCR recognition CD3 CD3 B 8 Y E + + O O + ITAMs signaling ITAM = Immunoreceptor Tyrosine-based activation motif E

TCR Heterodimers and Immunoglobulins

1. TCR heterodimers are similar to immunoglobulins
2. Therefore they are classified in immunoglobulin superfamily
3. Resembles Fab fragment

B-cell migM L chains NH2 VL VI NH2 CL C VH VH aß T-cell receptor a-chain B-chain NH2 NH2 H chain H chain -s-g Va VB -5-5- CB Connecting sequence Transmembrane region (Tm) + + + Cytoplasmic tail (CT) COOH (248) COOH (282) 2000 W H Freman and Company

T Cell Receptor Ligands

1. MHC proteins + antigenic (non-self) peptide
2. 2 classes of MHC protein -> Class I and Class II
3. Class I on surface of all nucleated body cells
4. Class II on surface of antigen presenting cells (APCs)

T Cell Ligand Recognition

1. T cells MUST distinguish between peptides derived from self and non-self proteins
2. CD8 co-receptors recognise invariant parts on MHC Class I proteins
3. CD4 co-receptors recognise invariant parts on MHC Class II proteins

MHC Class I and II Ligand Binding

MHC class II MHC class I CD4 CD8 a b D4 CD4 CD8 D3 MHC class I MHC class II D2 Q1 ₿1 α1 D1 B2 OL2 Q3 ₿2- micro- globulin C d Figure 4.25 Janeway's Immunobiology, 8ed. (@ Garland Science 2012) a

T Cell Receptor vs B Cell Receptor

1. T cell receptor is only membrane bound
2. Antigen binding of T cell receptor is weaker than that of antibodies
3. Antigen recognised by T cells is not antigen alone but antigen associated with MHC molecules

Generation of TCR Diversity

1. Multiple germ-line gene segments · Combinatorial V-(D)-J joining · Junctional flexibility · P-region nucleotide addition · N-region nucleotide addition . Combinatorial association of light and heavy chains
2. However, there is no somatic mutation with TCR . May be to ensure that after thymic selection, the TCR doesn't change to cause self-reactive T cells

Alloreactivity of T Cells

1. Allogeneic - genetically different individuals of same species
2. Alloreactivity of T cells is puzzling:
3. Evidence supports that T cells can only respond to antigen+MHC
4. However, T cells can recognise a foreign MHC molecule alone - As with transplants

Summary of T Cell Receptors

1. T cell receptors (TCRs) are integral to the adaptive immune system, recognising peptide antigens presented by major histocompatibility complex (MHC) molecules.
2. Structurally, TCRs are composed of alpha and beta (or gamma and delta) chains, with variable regions that interact specifically with peptide-MHC complexes.
3. The diversity of TCRs is essential for the immune system's ability to recognise a wide range of antigens.I KNIVEDOITV .-

T Cell Development and Activation

Learning Objectives

On completion of this session you should be able to

1. Describe the stages of T cell development from hematopoietic stem cells in the bone marrow to mature T cells in the thymus.
2. Recognise positive and negative selection in T cell development.
3. Describe the process of T cell activation.
4. Understand T cell-mediated immune responses.

T Cell Development Stages

1. T cells develop from stem cells in the bone marrow but complete their maturation in the thymus
2. Thymus comprises lobules containing an outer cortex and inner medulla
3. Stages of development are indicated by the presence/absence of cell surface markers (TCR:CD3, CD4, CD8)

Thymus Structure

thymus lung (heart capsule 0 trabeculae cortical epithelial cell Cortex- sub- capsular epithelium thymocyte (bone marrow origin) cortico- medullary junction medullary epithelial cell Medulla dendritic cell (bone marrow origin) Hassall's corpuscle macrophage (bone marrow origin) Figure 8.15 Janeway's Immunobiology, 8ed. (@ Garland Science 2012)

T Cell Precursor Development

1. T-cell precursors originate in the bone marrow, but all the important events in their development occur in the thymus
2. T-cell precursors proliferate extensively in the thymus, but most die there
3. Thymocytes then commit along y:8 or a: p lineages
4. a:3 T cells develop into two distinct functional subsets-CD4 T cells and CD8 T cells
5. This generates T cells that recognise self- MHC (positive selection) and are self- tolerant (negative selection)

CD3-4-8 'double-negative' thymocytes y:8+CD3+ CD4-8 CD3+pTa:B+4+8+ large active 'double-positive' thymocytes Export to periphery CD3+a:B+4+8+ small resting 'double-positive' thymocytes <5% CD4+8- CD4 8+ small resting 'single-positive' thymocytes Export to periphery

Positive Selection in T Cell Development

1. Positive selection:
2. Occurs in thymic cortex
3. Mediated by thymic cortical epithelial cells that express both MHC class I and II proteins
4. If thymocyte fails to recognise an MHC molecule within 3 - 4 days of initial a: p expression, the cell dies
5. Cortical epithelial cells deliver a survival signal

Co-receptor Selection

1. Co-receptor selection:
2. Recognition of an MHC molecule by one co-receptor induces downregulation of the other co-receptor gene
3. Thus, CD4LOW CD8HIGH survive if they recognise MHC class I molecules and CD4HIGH , CD8LOW survive if they recognise MHC class II molecules
4. Mediated cortical epithelial cells that deliver a maturation signal when co-receptor recognition occurs

Negative Selection in T Cell Development

1. Negative selection:
2. Occurs in thymic cortex and medulla
3. Mediated by cortical epithelial cells and macrophages and dendritic cells
4. If thymocyte recognises self peptide: MHC complex strongly, it dies
5. Different binding affinities to MHC-peptide mediate survival (positive selection) or death (negative selection)
6. Self peptides are derived from thymic proteins and ubiquitous proteins via the blood
7. Thus, cells surviving positive, co-receptor and negative selection are single positive, self tolerant naïve T cells

T Cell Activation Process

1. Recognition of MHC:peptide complex on DCs i.e. antigen recognition
2. Co-stimulatory signal delivered - B7:CD28
3. Cells enter cell cycle (G ) -> proliferation (clonal expansion)
4. Mediated by IL-2
5. IL-2 mediates proliferation & differentiation into effector cells
6. Cytokines expressed by APCs determine the effector cell type the T cell will become

APCs and Naive T Cell Signals

APCs deliver three kinds of signals to naive T cells APC B7.1 MHC class II cytokines IL-6 B7.2 IL-12 TGF-B IL-4 TCR CD28 CD4 1 2 3 T cell Activation Survival Differentiation Figure 9.19 Janeway's Immunobiology, 8ed. ( Garland Science 2012)

T Cell Mediated Immunity

1. Naive T cells circulate between blood and lymphatics: Blood CD8+ T cell CD4+ Ţ cell Lymphatics + Antigen co-stimulation CD 8+ Tc Cells CD 4+ T_1/T_2/T cells FH
2. Mediated by cell adhesion molecules (CAMs)
3. T cells monitor MHC:peptide complexes on APCs in lymphoid tissue

Summary of T Cell Development and Activation

1. T cell development involves a complex process from hematopoietic stem cells in the bone marrow to mature T cells in the thymus.
2. Positive selection ensures survival of T cells that recognise self- MHC molecules, while negative selection eliminates those with high affinity for self-antigens.
3. T cell activation, triggered by antigen recognition and co- stimulation, leads to differentiation into effector T cell subsets.
4. T cells play pivotal roles in immune defence, combating intracellular pathogens, cancer cells, and infected host cells.I KNIVEDOITV .-

T Cell Functions

Learning Objectives

On completion of this session you should be able to

• Recognise the functions of different T cell subsets.
• Comprehend the importance of T cells in immune regulation and defence.

Effector T Cells - General Properties

1. Armed effector T cells leave the lymphoid tissue and migrate to sites of injury/infection via the blood
2. They migrate to the tissues via activated endothelium
3. Scan tissues for MHC:antigenic peptide ligands
4. Antigen recognition triggers effector function (do not require co- stimulation)
5. Interaction of TCR with antigenic ligand has 2 effects: i) Cytoskeleton re-organises to focus effector molecules onto target cell ii) Triggers release of effector molecules
6. Effector mechanisms mediated by both cell surface and soluble molecules

CD4+ T Cell Differentiation

1. Cytokines produced by APCs determine CD4+ T cell differentiation
2. Determines whether cell mediated or humoral responses dominate
3. IL-6 burst associated with TEL cell development
4. IL-12 and IFN-y associated with T_1 cell differentiation
5. IL-4 associated with T_2 cell differentiation