Unit 2 seminar: Adaptive immunity T & B lymphocytes Reminders: -Use references in discussion and be sure to rephrase information in your own words -Evaluate the quality of reference materials before using

T lymphocytes (T cells) Develop in the thymus Stem cells from bone marrow migrate to thymus in fetal life Early thymocytes develop from stem cells in the thymus cortex Late thymocytes develop from early thymocytes in the thymus medulla T cells develop from late thymocytes in the medulla Maturation and release occurs along with the training to differentiate self from non-self ◦ Positive selection ◦ Negative selection (apoptosis)

T cells - TCR complex TCR ( T Cell Receptor complex) T cell receptor- antigen specific - ◦ Has 2 chains -  &  ◦ Has constant and variable domains ◦ Structure like immunoglobulin light chain CD3 receptor- carries signal from the cell membrane to the cell cytoplasm CD4 or CD8 receptors- determine the function of T cell

T cell receptor Antigen specific receptor on T cell Heterodimer (  &  ) chains- Two external domains each- C , C , V  and V  a transmembrane segment Cytoplasmic extension

CD receptors T cell differentiation markers (CD= Cluster of Differentiation) Mature T cells- 4 important types CD2, CD3, CD4 and CD8 CD2- Present on all peripheral T cells ◦ receptor for attachment to cells CD3 - Associated with TCR ◦ consists of 5 molecules ( , ,  and two  ) ◦ Transduces signals across the membrane.

CD receptors ( Contd.) CD4 receptors ◦ present mainly on T helper cells ◦ Interact with MHC class II antigens ◦ target for HIV ( AIDS virus) CD8 receptors ◦ present mainly on T-cytotoxic and T suppressor cells ◦ recognize MHC class I antigen

Other accessory molecules of T cells CD 28- Costimulation- signal transduction CTLA-4:Signal transduction LFA-1: Adhesion VLA-4: Adhesion

T cell accessory molecules (Fig 5-3 B)

Antigen doesn’t bind directly to TCR. T cell receptor and CD receptor work together to interact with peptide (from antigen processing) and MHC molecules

T cell - subtypes T helper/inducer cells ( T H ) T suppressor cells ( Ts) T cytotoxic cells (CTL or Killer cells) T cells involved in Delayed type of hypersensitivity( T DTH ) T memory cells ( Usually a subset of T helper cells)

T helper/inducer cell CD4 receptor Function- ◦ Recognize antigen epitope in conjunction with MHC class II antigen ◦ Reacts with IL1 (interleukin-1) from macrophages ◦ Produces IL2 and expresses IL2 receptors ◦ Is activated by IL2 ◦ Stimulate B cell growth and differentiation with a variety of lymphokines.

T suppressor cell Has CD8 receptors Function- ◦ Interacts with MHC class I receptors on the cells ◦ Inhibits and regulates B cell differentiation into plasma cells ◦ Activated by products of T helper cells, IL2.

T cytotoxic cells (Tc) Killer cells Possess CD 8 receptors Function ◦ Cell mediated cytotoxicity ◦ Develop after IL2 activation ◦ require MHC class I receptors for recognition of foreign antigen

T DTH- Delayed Type of Hypersensitivity Possess CD4 receptors Require lymphokines for their activation ( IL1, IL2 and  interferon) Function ◦ Immunity against  Fungi  Mycobacterium leprae  Chronic infections ◦ Delayed type of hypersensitivity ◦ Major component of granulomatous lesions.

B lymphocytes Develop from stem cells in Bone marrow Unique S-Ig receptor for antigen ( can be of any type of Ig) Differentiate into Plasma cells for production of antibodies. Receptors- Surface Immunoglobulin ◦ 100,000 copies per cell ◦ undergoes capping and endocytosis after combining with antigen

Plasma cell Terminally differentiated B cells Ovoid shape eccentric spoke-wheel nucleus Intensely basophilic cytoplasm Average life span less than 4 days Mostly present in lymphoid tissues Produce only one type of antibody

Normal circulation of lymphocytes and other immune cells Lymphocytes and macrophages do circulate through different organs. Lymphocytes are the only cells allowed in the CNS But they tend to localize back into the sites they originated from, with the help of lymphocytic homing molecules or vessel addressins

Points to discuss Definition Types of cytokines Sources of cytokines Chemokines Interferons Interleukins Tumor Necrosis Factors Cytokine receptors Therapeutic applications of cytokines

Cytokine- Definition & General properties Cytokines are low molecular weight proteins which act as intercellular communication molecules. They mostly act in autocrine and paracrine manner. A few may act in an endocrine manner. They are produced mainly by immune system cells but can also be produced by many other cells.

Types of cytokines Most of these are generally called cytokines If they are produced by lymphocytes predominantly, they are sometimes referred to as Lymphokines If they are produced by monocytes predominantly, they are sometimes referred to as Monokines

Types of cytokines Chemokines- involved in chemotaxis Interferons- Inhibitory factors Interleukins- Mostly cell messenger function Tumor necrosis factors- mainly apoptosis signals or cell lytic function Colony stimulating factors (CSFs) Sometimes interleukins and CSFs are included in a broader family of hematopoietins

Chemokines Chemokines- The cytokines which aid in chemotaxis of phagocytes mainly. Examples ◦ IL8, TNF-alpha - for neutrophils ◦ MIP-beta : for macrophages

Interferons 3 types Alpha IFN & Beta IFN - secreted by leukocytes, fibroblasts and other cells infected by a virus ◦ make the host cells resistant to viral invasion and inhibits viral multiplication Gamma IFN - secreted by lymphocytes to activate the macrophages to enhance intracellular killing.

Interleukins So far IL 1 to IL 25 have been significantly characterized. Many more are being investigated. A few key interleukins are IL1, IL2, IL4 and related interleukins. Many of these can induce acute phase reactants from liver

Interleukin 1 Secreted mainly by macrophages, also by endothelium and epithelial cells Endogenous pyrogen- fever –signals hypothalamus Lymphocyte proliferation and activation Expression of selectins by endothelial cells and increased adhesion of leukocytes

Interleukin 2 Secreted by activated lymphocytes (TH1) autocrine and paracrine action T helper cell proliferation T cytotoxic cell activation & proliferation Natural Killer cell activation

Interleukin 4 family (IL4,5,10,14) Secreted by T lymphocytes and mast cells Predominant in TH 2 responses Stimulate IgE production (esp. IL 5) involved in allergic phenomena

Interleukin 6 Secreted by activated T cells, monocytes, fibroblasts and endothelial cells Progenitor cell stimulation Platelet production Immunoglobulin production in B cells.

Tumor necrosis factors TNF alpha- ◦ Secreted by macrophages, lymphocytes and other cells ◦ Chemotactic for neutrophils ◦ Inflammation and fever ◦ Cytotoxic for some tumor cells TNF beta- ◦ T lymphocytes (esp. T cytotoxic cells) and natural killer cells ◦ Cytotoxic for target cells

Cytokine receptors Many different types One receptor can interact with many different cytokines One cytokine can interact with different receptors when a cytokine attaches to a receptor it will induce intracellular messenger which in turn can induce gene transcription change.

Examples of Cytokine receptors Interleukin receptors e.g. IL2R TNF receptor family Interferon receptor family Immunoglobulin family Chemokine receptor family.

Therapeutic uses of cytokines Receptor antagonists- antibodies or mimic molecules- rheumatoid arthritis e.g Enbrel, Remicade Interferons- Hepatitis B, C, Kaposi’s sarcoma, Multiple sclerosis, melanoma Colony stimulating factors- After bone marrow transplants

Development of T Lymphocytes (Fig 4-13)

T cell receptor (Fig. 4-5)

Recognition of a peptide epitope nestled in MHC class I molecule by TCR Recognition of a peptide epitope nestled in MHC class I molecule by TCR

Maturation of lymphocytes (Fig 4-8)