Cell-Mediated Immunity CMI Specialized lymphocytes, mostly T cells, respond to intracellular Ags After differentiating in the thymus, T cells migrate to lymphoid tissue T cells differentiate into effector T cells when stimulated by an Ag Some effector T cells become memory cells

T Cells Helper T Cells (CD4, TH) Cytotoxic T Cells (CD8, TC) TH1 Activate cells related to cell-mediated immunity TH2 Activate B cells to produce eosinophils, IgM, and IgE Cytotoxic T Cells (CD8, TC) Destroy target cells with perforin

T Cells Delayed Hypersensitivity T Cells (TD) (CD4) Associated with allergic reaction, transplant rejection, and tuberculin skin test Suppressor T cells (TS) (CD8) Turn off immune response when Ag no longer present

Structure of T Cell Receptor CHO Variable region “V” Constant region “C” Hinge “H” Alpha chain Beta chain Disulfide bridge Transmembrane region Cytoplasmic tail +

Structure of T Cell Receptor (TCR) Two polypeptide chains, α and β, of roughly equal length Both chains consist of a variable (V) and a constant (C) region α chain V region has a joining (J) segment β chain V region has both a J and diversity (D) segment

Structure of T Cell Receptor (continued) Hypervariable regions in V contribute to diversity of TCR TCR recognizes portions of MHC molecule and peptide bound in the groove

What Does the T Cell Receptor (TCR) Recognize? Only fragments of proteins (peptides) associated with MHC molecules on surface of cells Helper T cells (TH) recognize peptide associated with MHC class II molecules Cytotoxic T cells (Tc) recognize peptide associated with MHC class I molecules

Interactions of TH Cell and APC T helper lymphocyte TCR LFA-2 LFA-1 CD28 TNF-alpha IL-1 IL-6 IL-12 IL-15 TNF-beta IFN-gamma GM-CSF IL-4 CD4 peptide Antigen- presenting cell LFA-3 ICAM-1 Class II MHC B7-1/B7-2 (CD80/CD86

Interactions of Tc Cell and Target Cell T cytotoxic lymphocyte LFA-1 TCR LFA-2 CD8 peptide Target cell ICAM-1 Class I MHC LFA-3

T-independent Antigens B cell Figure 17.17

T-Dependent Antigens Figure 17.16

T-dependent and independent antigens

Self MHC Restriction T cells recognize foreign antigen associated with self MHC No value for individual to have T cells that recognize foreign antigen associated with foreign MHC Self MHC restriction occurs in thymus

Process of Self MHC Restriction in Thymus T cells with TCR recognizing self MHC molecules are retained – “positive selection” Retained T cells with TCR recognizing self peptide associated with self MHC are eliminated – “negative selection” Self MHC-restricted T cells are released

Dendritic cells present antigens Figure 17.12

Helper T Cells Figure 17.13

Cell-mediated Cytotoxicity Figure 17.14

Nonspecific Cells Activated macrophages: Macrophages stimulated by ingesting Ag or by cytokines Natural killer cells: Lymphocytes that destroy virus-infected cells, tumor Figure 17.15

Self MHC Restriction in the Thymus 4 - 8 low 4 low 8 low Sub-capsular region Productive TCR rearrangement Non-productive TCR rearrangement APOPTOSIS 4 + 8 + TCR Not recognise self MHC Recognise self MHC macrophage 4 + 8 + TCR TCR recognises self antigens Cortex TCR does not recognise self antigens Negative selection Cortico-medullary region 4 - 8 - 4 + 8 + TCR 4 + 8 - TCR 4 - 8 + vessel Medulla

Self MHC Restriction in the Thymus 4- 8- 4+/- 8+ 4+ 8+ TCR low Express MHC I MHC II No MHC engagement apoptosis TCR high 4+

Self MHC Restriction in the Thymus No interaction with self antigen Interaction with MHC I and self antigen. Interaction with dendritic cells, macrophages and medullary epithelium Interaction with MHC II 8+ TCR high 4+ TCR induced apoptosis Mature T cell pool

Self MHC Restriction in the Thymus

T-Cell clonal selection Animation

Superantigens Proteins produced by pathogens Not processed by antigen presenting cells Intact protein binds to variable region of β chain on TCR of T cells and to MHC class II on antigen presenting cells (APC) Large numbers of activated T cells release cytokines having pathological effects

Conventional Antigen Superantigen αC βC βV αV α2 β2 β1 α1 MHC Class II CHO βV αV α2 β2 β1 α1 MHC Class II T cell receptor Antigen Super antigen T lymphocyte Antigen presenting cell