T-Cells and Immune Response

Leukocytes

• Leukocytes can be divided into granulocytes and agranulocytes.
• Granulocytes consist of neutrophils, eosinophils, and basophils.
• Agranulocytes consist of monocytes and lymphocytes.
• Monocytes differentiate into macrophages.
• Lymphocytes consist of B cells, T cells, and natural killer cells.

Lines of Defense

• The immune system is the third line of defense against infection.
• The first line of defense consists of skin, mucous membranes, and their secretions.
• The second line of defense consists of phagocytic white blood cells, antimicrobial proteins, and the inflammatory response.
• The third line of defense is a specific defense mechanism that consists of lymphocytes and antibodies.

Lymphocytes

• Lymphocytes are a type of white blood cell, also known as leukocytes.
• Most lymphocytes are small, featureless cells with few cytoplasmic organelles and inactive nuclear chromatin.
• Lymphocytes can be divided into three main types: large granular lymphocytes, small lymphocytes, B cells and T cells.
• Large granular lymphocytes are part of the innate immune system and are natural killer cells (NKCs).
• Small lymphocytes are the main agents of the acquired immune system.
• Lymphocytes are surrounded by a thin cytoplasm containing some mitochondria, free ribosomes, and a small Golgi apparatus.
• Lymphocytes can mainly be found in lymphoid organs, in blood and are scattered under mucosal surfaces.
• Central lymphoid organs include the thymus (where T-cells mature) and bone marrow (where B-cells develop).
• Secondary lymphoid organs include the lymph nodes, spleen, adenoids, tonsils, appendix, Peyer's patches.

B-Cells

• B-cells and T-cells are the two major types of lymphocytes.
• B lymphocytes, sometimes referred to as B cells and often named on lab reports as CD19 or CD20 cells, differentiate into plasma cells that secrete antibodies when activated.
• B-cells develop in the bone marrow from hematopoietic stem cells.
• When mature, B-cells can be found in the bone marrow, lymph nodes, spleen, certain regions of the intestine, and the bloodstream.
• When B-cells encounter foreign material (antigens), they respond by maturing into plasma cells.
• B-cells can also mature into memory cells, allowing for a rapid response if the same infection occurs again.
• Plasma cells are the mature cells that produce antibodies.
• Antibodies, which are the major product of plasma cells, circulate in the bloodstream, tissues, respiratory secretions, intestinal secretions, and even tears.
• Antibody molecules are specifically designed to bind to each foreign antigen, similar to a lock and key.
• When antibody molecules recognize a foreign microorganism, they physically attach to it and trigger a series of events involving other components of the immune system to destroy the germ.
• Antibodies vary in their specialized functions determined by their chemical structure which determines the class of the antibody (or immunoglobulin).
• There are five major classes of antibodies: IgG, IgA, IgM, IgD, and IgE.
• IgG has four different subclasses: IgG1, IgG2, IgG3, IgG4.
• IgA has two subclasses: IgA1 and IgA2.
• Each immunoglobulin class has distinct chemical characteristics that provide it with specific functions.

T-Cells

• T-cells, sometimes referred to as T-lymphocytes and often named in lab reports as CD3 cells, are another type of immune cell.
• T-cells directly attack cells infected with viruses and act as regulators of the immune system.
• T-cells develop from hematopoietic stem cells in the bone marrow, but complete their development in the thymus.
• Mature T-cells leave the thymus and populate other organs of the immune system, such as the spleen, lymph nodes, bone marrow, and blood.
• Each T-cell reacts with a specific antigen, similar to how each antibody molecule reacts with a specific antigen.
• T-cells have molecules on their surfaces that are similar to antibodies called TCR and BCR.
• The variety of different T-cells is so extensive that there are T-cells that can react against virtually any antigen.
• Types of T Cells:
  • Helper T cells (Th), often denoted in lab reports as CD4 T-cells.
  • "Killer" or cytotoxic T-cells (Tc), often denoted in lab reports as CD8 T-cells.
  • Suppressor T-cells or Regulatory T-cells (Treg).
• Each type of T-cell has a different role to play in the immune system.
• T-cells Functions:
  • Helper T-cells assist B-cells to produce antibodies and assist killer T-cells in their attack on foreign substances.
  • Killer, or cytotoxic, T-cells perform the actual destruction of infected cells and protect the body from certain bacteria and viruses that have the ability to survive and even reproduce within the body's own cells.
  • Regulatory T-cells suppress or turn off other T-lymphocytes, and without them, the immune system would keep working even after an infection has been cured.

Lymphocyte populations

• Major Peripheral Blood Lymphocyte Populations in Domestic Animals and Humans

Natural Killer Cells

• Natural killer (NK) cells easily kill cells infected with viruses.
• NK cells do not require the same thymic education that T-cells require, which is why they are called "natural killer" cells.
• NK cells are derived from the bone marrow and are present in relatively low numbers in the bloodstream and in tissues.
• NK cells are important in defending against viruses, possibly preventing cancer, and are thought to be important in the innate immune defense against intracellular pathogens.

Lymphocyte Mitogens

• A mitogen is a chemical substance that encourages a cell to commence cell division, triggering mitosis.
• A mitogen is usually some form of a protein.
• B cells can enter mitosis when they encounter an antigen matching their immunoglobulin.
• Mitogens are often used to stimulate lymphocytes and therefore assess immune function.
• Lectines are proteins that bind to cell surface glycoproteins and so trigger cell division.
• Not all lymphocytes respond equally well to all lectines.

Adaptive Immunity:

• Adaptive immunity has 2 types: humoral and cell-mediated immunity
  • Humoral immunity eliminates extracellular microbes by using:
    • B lymphocytes
    • Antibody secretion
    • Block infections and eliminate extracellular microbes
  • Cell-mediated immunity eliminates intracellular microbe by using:
    • Helper and Cytotoxic T lymphocyte
    • Activation of macrophages to kill phagocytosed microbes
    • Kill infected cells and eliminate reservoirs of infection

Antigen Presentation to T Lymphocytes

• In an adaptive immune response, antigen is recognized by two distinct sets of highly variable receptor molecules with immunoglobulins that serve as antigen receptors on B cells and the antigen-specific receptors of T cell.
• T cells only recognize antigens that are displayed on cell surfaces and can detect the presence of intracellular pathogens.
• Infected cells display on their surface peptide fragments derived from the pathogen's proteins.
• Foreign peptides are delivered to the cell surface by specialized host-cell glycoproteins, the MHC molecules.
• T-cell receptor differs from the B-cell receptor because it does not recognize and bind antigen directly. It recognizes those of short peptide fragments of pathogen protein antigens bound to MHC molecules on the surfaces of cells.
• MHC can also be called:
  • Human (HLA)
  • Cow (BOLA)
  • Horse (ELA)
  • Sheep (OLA)
  • Mice (H-2 Complex)
• Both types of MHC proteins: MHC class 1 and class II are important to T cell activation

Antigen presenting cells (APC)

• Major APCs are dendritic cells (DCs), macrophages, and activated B cells.
• The major initiators of adaptive immunity are DCs, which actively migrate to the lymph nodes and secondary lymphoid organs and present antigens to T and B cells.
• Macrophages are specialized to internalize extracellular pathogens, especially after they have been coated with antibody, and to present their antigens.
• B cells have antigen-specific receptors that enable them to internalize large amounts of specific antigen, process it, and present it.

Immunity Response

• First stage of Antigen processing is to disclose the epitope:
  • Antibodies will bind to epitopes displayed on the surface of antigens
  • Epitopes recognized by T-cell receptors are often buried
  • The antigen have to be broken down into peptide fragments
  • That peptide will bind to a self molecule known as MHC molecule -The T-cell receptor binds to a complex of MHC molecule and epitope peptide
• Second stage of antigen processing:
  • presenting of antigen by MHC to T-cells.

MHC Proteins:

• Class I MHC proteins:
  • Are always recognized by CD8 T cells
  • Display peptides from endogenous antigens that are egraded by proteases and enter the endoplasmic reticulum
  • Are Transported via TAP (transporter associated with antigen processing)
  • Loaded onto class I MHC molecules
  • Displayed on the cell surface in association with a class I MHC molecule
• Class II MHC proteins:
  • Are found only on mature B cells, some T cells, and antigen-presenting cells
  • Always recognized by CD4 T cells
  • When a phagosome containing pathogens (with exogenous antigens) merges with a lysosome class II MHC proteins are activated
  • Invariant protein prevents class II MHC proteins from binding to peptides in the endoplasmic reticulum
  • CLIP removed by HLA-DM

Co-receptors of MHC class I and II

• Th (T-Helper) contains specific molecule called CD4.
• Tc (T-Cytotoxic) & Treg contains specific molecule called CD8.

T Cell Activation

• T Cell Activation required two independent signals:
  • Binding of the peptide:MHC complex by the T-cell receptor, the CD4 co-receptor will transmit a major signal to the T cell that antigen has been encountered
  • Activation of naive T cells requires a second signal: the co-stimulatory signal, and that should be delivered by the same antigen-presenting cell
  • These signals will play a important role of differentiation of T-cells.
• Binding of the T-cell receptor (TCR) and its co-receptor CD4 to the peptide:MHC class delivers a signal that can induce the clonal expansion of T cells only when the co-stimulatory signal is given by binding of CD28 to B7 molecules.
• APCs deliver three kinds of signals to naive T cells and CTLA-4 binds B7 more avidly than CD28 does, therefore delivering inhibitory singals to activated T cells

Helper T Cells (TH)

• Helper T cell recognizes complex of antigenic peptide with MHC class II and activates a B cell
• Regulatory cells that play a central role in the adaptive immune response. stimulates proliferation of other T cells.
  • Stimulates B cells that have already become bound to antigen.
• Without Th, there is no immune response.
• Helper T-cells are responsible for cell-mediated immunity (attack on infected cells) and humoral immunity (secretion of antibodies by plasma cells).

B-Cell Activation

• The humoral immune response is mediated by antibody molecules that are secreted by plasma cells.
• First stage:
  • Antigen that binds to the BCR signals B cells and is internalized and processed into peptides
  • This in result activates armed helper T cells
• Second stage:
  • Antibodies induced will protect the host from infection in three main ways
    • They can inhibit the toxic effects or infectivity of pathogens by binding to them: this is termed neutralization -By coating the pathogens, they can enable accessory cells that recognize the Fc portions of arrays of antibodies to ingest and kill the pathogen, a process called opsonization
    • Antibodies can also trigger activation of the complement system. Complement proteins can strongly enhance opsonization, and can directly kill some bacterial cells
• B cells presents the antigen to helper T cells which are activated and produces the CD40 ligand and cytokines, and in result activates the B cell
• The most specific interaction is with an antigen-binding B cell with and armed B-cell stimulatory molecule CD40 ligand on the helper T-cell surface and to the secretion of the B-cell stimulatory cytokines that drive the proliferation and differentiation of the B cell into antibody-secreting plasma cells.

Explore the roles of helper, regulatory, and killer T-cells in immune responses. Understand T-cell vs. B-cell development, the function of lymphoid organs, and the role of hematopoietic stem cells. Identify the impact of low CD8 T-cell counts.