T-Helper Cells

• After Helper T-cells are activated, the antigen-presenting cell that the Helper T-cell is attached to will secrete cytokines into the immune synapse, determining which type of Helper T-cell it will become.
• The cell will create many clones of itself after it has become a helper T-cell to combat the pathogen.

T-helper cells

• Includes these categories:
  • T-helper type 1 (Th1)
  • T-helper type 2 (Th2)
  • T-helper type 17 (Th17)
  • T follicular helper cells (Tfh)
  • T regulatory (Tregs)
• Cytokines originate from antigen-presenting cells.
• The type of pathogen present determines which antigen-presenting cells are used, helping to tailor the immune response to the specific pathogen.

Types of T-Helper Cells

• When cytokines activate these cells, they trigger genetic changes through transcription factors.
• The specific helper T-cell then secretes its own cytokines to perform its functions.

Th1 Cells

• Th1 Cells generally enhance macrophages' ability to kill organisms, increasing the proliferation of NK cells, Cytotoxic T-cells, and B cells.
• Cytokines bind to the T cell receptor, causing it to make transcription factors that cause the T cell to transform into a Th1 cell.
• Cytokines originate from macrophages and dendritic cells infected with viruses and intracellular bacteria, natural killer cells, and cells infected with viruses.
• A Th1 cell secretes interferon-gamma, which boosts macrophages’ ability to kill ingested pathogens via the oxidative burst.
• This increases the production of reactive oxygen species like nitric oxide and lysosomal proteases.
• Th1 cells express CD40 ligand on their cell surface, which binds to the CD40 receptor on macrophages, stimulating them.
• Th1 cells produce IL-2, which makes natural killer cells, CD8+ T cells, and B cells proliferate.

Th2 Cells

• Th2 cells augment IgE production by B-cells, in turn coating worms with antibodies and stimulating cells to release their granules.
• The cytokine that the Th2 releases will also recruit eosinophils to the site of the parasitic infection.
• They combat parasitic infections.
• Macrophages and dendritic cells exposed to a parasitic worm secrete cytokines that bind to T cell receptors, causing it to create transcription factors that cause the T cell to transform into a Th2 cell.
• Th2 cells produce cytokines that stimulate B cells to make IgE.
• IgE coats parasitic worms.
• IL-5 recruits eosinophils to the site of infection, where they accumulate and degranulate, thus killing the parasite.
• Th2 cells stimulate mast cells and basophils to bind to the Fc region of IgE.
• This signals those cells to degranulate and kill the parasite.

Th17 Cells

• Secreted cytokines recruit neutrophils.
• They combat bacterial and fungal infections.
• Dendritic cells and macrophages that have interacted with extracellular bacteria and fungi stimulate T cells to become Th17 cells.
• Th17 cells recognize bacterial peptidoglycans, lipopeptides, and fungal glycans.
• Th17 cells produce IL-17, which works to recruit neutrophils to engulf and destroy extracellular pathogens.

T Follicular Helper Cells

• T Follicular Helper Cells enhance memory cell and IgG-producing plasma cell production.
• They reside in the follicles of lymph nodes.
• Antigen-presenting cells produce cytokines that stimulate a T cell to become a Tfh cell.
• T-follicular helper cells then stimulate a B cell to transform into a Plasma cell that produces IgG.
• Tfh cells express CD40 ligand on their cell surface that binds to CD40 receptor on B cells, making them express cytokine receptors.
• Tfh cells produce IL-21 and interferon-gamma, which stimulate B cells to differentiate into memory cells and plasma cells that make IgG antibodies.

Cytotoxic T Cells (CD8 Cells)

• An activated cytotoxic T cell doesn't need the costimulatory signal from CD28 to proceed with its functions and only needs to see its antigen in an MHC I molecule to kill the cell.
• Cytotoxic T cells locate potential targets by binding cell-to-cell non-specifically.
• They use adhesion molecules like LFA-1 on their surface to bind to molecules like ICAM, found on the surface of most cells.
• If the cytotoxic T cell cannot bind because the correct antigen isn’t present, it disengages and moves on to the next cell.
• If the cytotoxic T cell binds to the antigen, the two cells engage with each other more strongly.

Attachment

• The cytotoxic T cell recognizes its antigen in the MHC I molecule.
• It binds to the infected cell via an “adhesion molecule” (LFA-1) that binds to a molecule (ICAM) found on the surface of most cells in the body.
• Binding to the antigen in the cell’s MHC I molecule causes the LFA-1 molecule to change its confirmation to bind ICAM more tightly, forming a "death embrace."
• The cytoskeleton rearranges and forms the supramolecular activation cluster (SMAC) on its surface.

Killing

• The cytotoxic T cell releases its granules, which contain perforin and granzymes.
• Perforin punches holes in the lipid bilayer of the target cell.
• Granzymes trigger apoptosis in the target cell.
• The cytotoxic T cell disengages and moves on to another potential target cell.

Natural Killer Cells

• Natural killer cells are non-specific.
• They kill a target cell based on the number or strength of activating versus inhibiting signals they receive.
• They deliver granzymes and perforin, similarly to cytotoxic T cells.
• They are part of the innate immune response and don’t respond to antigens.
• They recognize cell surface molecules that are on the surface of our body’s cells infected with viruses, intracellular bacteria, or cancerous cells.
• Natural killer cells recognize MHC class I molecules that are part of our body and do not kill it.
• If the MHC I molecule is absent or foreign, they will kill the target cell.
• Many viruses try to hide from our immune responses by inducing their host cell to remove MHC class I molecules, thus causing the NK cell to kill it.
• Natural killer cells also kill a cell by antibody-dependent cell-mediated cytotoxicity (ADCC).
• When a cell infected with viral proteins is bound by IgG antibodies, the NK cell surface molecule CD16 binds to to Fc portion of the antibody, which signals the NK cells to destroy the infected cell.
• Natural killer cells also produce cytokines to activate macrophages.

Antibodies

• Antibodies are made by the plasma cells, after they have been activated.
• Antibodies attach to the antigen of only one specific pathogen.
• There are 5 major classes of immunoglobulins: IgM, IgD, IgG, IgA, and IgE.
• Each of these immunoglobulins has a different function, shape, and valence.

Immunoglobulin M (IgM)

• It is the first antibody produced in all immune responses.
• Makes up 4% of all antibodies found in the serum.
• Is the B cell receptor.
• Has 2 separate conformations
• When it Serves as B cell receptor, it binds 2 antigens with a valence of 2.
• When it is secreted as an antibody, it joins up with 4 other antibodies to form a pentamer structure.
• The pentamer structure is held together by a structure called the J chain.
• This pentamer structure can attach 10 antigens.
• IgM can be made without T cell help.
• Its production does not rely on being exposed to an antigen first.
• It can work against carbohydrates and lipid antigens.
• IgM is the most effective antibody at activating the complement pathway.

Immunoglobulin G (IgG)

• It is the most abundant immunoglobulin.
• Makes up 75% of immunoglobulin found in serum.
• Can bind to 2 antigens.
• Functions include:
  • Acts as an opsonin, which coats pathogens with antibodies, making it easier for phagocytes to pick them up and eat them.
  • Activates the complement pathway, particularly, the "classical" pathway which destroys extracellular pathogens, like bacteria
  • Works with NK cells to perform “antibody dependent cell mediated cytotoxicity,” where IgG binds to antigens on a viruses’ surface, the NK cell uses its CD-16 receptor to bind to the antibodies, and when two CD-16 molecules have bound to an antibody attached to the virus, the NK cell releases granzymes and perforin to kill the target cell.
  • Transports maternal IgG across the placenta to protect newborn babies from bacteria and viruses for 6 months.

Immunoglobulin A (IgA)

• Makes up 20% of the serum immunoglobulin.
• In the bloodstream, IgA exists as one structure that can bind 2 antigens (is a monomer).
• It is the primary antibody in mucosal sites, structures in the body lined with mucosal membrane.
• IgA is found in saliva, tears, breastmilk, and semen
• In mucosal sites, plasma cells produce IgA antibodies as dimers, two IgA molecules bound together, which can bind 4 antigens with a valence of 4.
• They are bound together by a J chain.
• Functions as an opsonin, binding to and neutralizing pathogens where they enter the body.
• Enables the body to eliminate or destroy pathogens before they can enter the body, by sweeping pathogens away by cilia in the mucosal tract, excreting pathogens out the GI and GU tracts, or degrading pathogens in the stomach or mouth by enzymes.
• Babies receive IgA in breast milk to neutralizes pathogens in the GI tract.

Immunoglobulin E (IgE)

• Exists as a monomer with a valence of 2.
• Makes up only about 0.004% of the total serum immunoglobulin.
• IgE is a key element in mounting allergic and anti-parasitic responses.
• IgE binds to IgE receptors on mast cells, basophils, and eosinophils, triggering those cells to release granules and destroy large and complex pathogens, like worms and parasites.
• IgE can be inappropriately produced to non-pathogenic targets like peanuts or tree pollen.
• IgE binds to Fc epsilon receptors on mast cells, triggering degranulation and histamine release, increasing mucus production and vascular permeability, causing swelling and smooth muscle contraction.
• IgE plays roles in atopic dermatitis, seasonal allergies, and asthma.

Immunoglobulin D (IgD)

• Makes up less than 1% of the serum immunoglobulin.
• Exists as a monomer with a valence of 2.
• IgD is found alongside IgM antibodies on mature B lymphocytes.
• IgD signals they are ready to leave the bone marrow.

Structure of the B Cell Receptor

• The receptor is essentially an antibody.
• It has two heavy chains and two light chains.
• The Fragment-antigen binding region (Fab region) is the part of the B cell receptor that binds the antigen at the point where the ends of the heavy and light chains meet.
• Each B cell receptor has two Fab fragments.
• The Constant region/Constant fragment region (Fc) is the remainder of the heavy chain.
• Each B cell receptor has two identical heavy and light chains, resulting in two identical antigen-binding sites.
• Chains are linked via disulfide bonds.
• The two heavy chains are linked to each other, and each heavy chain is linked to a light chain.
• When a B cell develops into a plasma cell, the receptor gets secreted as an antibody with the exact same antigen specificity.

Heavy Chains and Immunoglobulin Isotypes

• The heavy chain changes as the B cell develops!
• There are 5 major types of heavy chains: mu, delta, gamma, alpha, and epsilon.
• These are the classes (isotypes) of immunoglobulins: IgM, IgD, IgG, IgA, and IgE
• The five types of immunoglobulins are encoded by heavy chain genes.
• Early/young B cell receptors are all IgM and expresses the mu heavy chain.
• As the B-cell matures, it will express IgD in addition to IgM, now considered a mature B-cell.
• A mature B-cell can travel in the lymphatic system, but is still considered naïve, meaning that is has not been exposed to an antigen yet.
• Alternative splicing is the process by which the cell expresses the heavy chain exons for both mu and delta.

Lymph Node Structure and Function

• Lymph nodes are scattered throughout the body.
• Millions of B cells, T cells, antigens, and antigen-presenting cells pass through these lymph nodes.
• Cells enter in two ways:
  • From lymphatics through an afferent lymphatic vessel.
  • From blood through high endothelial venules (HEVs), special endothelial cells at postcapillary sites of lymphoid organs that when lymphocytes pass through, can move through the endothelial cells and slip into the lymph node.
• The paracortical region is the first portion where cells enter and where the T cells remain.
• In the cortical region, the B cells migrate and form the primary lymphoid follicles.
• If a B cell gets activated, it replicates in the follicle to form a germinal center.
• A follicle with a germinal center is called a secondary lymphoid follicle.
• Antigens enter the lymph node through the afferent lymphatic vessel, and travel to the follicle to interact with B cells.

B cell “activation”

• B cell becomes “activated” through interaction with a pathogen (binding to the pathogen’s antigen) and interaction with a complement fragment.
• B cells recognize a wide variety of antigens, like peptides, carbohydrates, and lipids, and become activated by them without needing antigen presenting cells to present an antigen.
• The antigen crosslinks two+ B cell receptors, activating the B cell.
• During B cell Activation by the Complement System, C3d, from the complement system, binds to an antigen.
• The C3d-antigen complex then binds to CD21 on the B cell.
• If the B cell receptor is bound to an antigen and has a CD21 that’s bound to an antigen, this will initiate B cell activation.

ACTIVATED B CELL

• An activated B cell will differentiate into a plasma cell and secrete antibodies. including 5 different types of antibodies.
• B Cells need CD4+ T cells to start making antibodies (other than IgM).
• An activated B cell can become a plasma cell and make the IgM antibodies without T Cell activation.
• To make IgG, IgA, and IgE antibodies, the B cell needs to interact with a helper T cell (CD4+ cell) in a process called Isotype switching, which requires a change in the DNA in a one-way fashion.
• When the B cell presents antigen on an MHC class II molecule to a CD4+ T cell, the T cell expresses molecule CD40L on its cell surface, which binds to CD40 on the B cell surface.
• This makes the B cell express cytokine receptors and makes the T cell secrete cytokines that instruct the B cell on the type of antibody to start producing.
• T cell secretion of IL-4 and IL-5 causes the B cell to become an IgE secreting plasma cell.
• T cell secretion of IFN-gamma causes the B cell to become an IgG secreting plasma cell.