Immunology Overview Kristine Krafts, M.D.

Immunology Overview Definitions Cells Lymphocytes Antigen-presenting cells Effector cells Responses The innate immune response Capturing and displaying antigens Cell-mediated immunity Humoral immunity Immunologic memory

Immunology Overview Definitions

Definitions Immunity = protection against infections Immune system = collection of cells and molecules that defend us against microbes Immune deficiencies → infections Immune excesses → autoimmune diseases

Innate (Natural) Immunity Always present (innate); doesn’t change over time First line of defense when bugs come Major components: Epithelial barriers (skin, GI, respiratory) Phagocytes NK cells Complement

Adaptive (Acquired) Immunity Second line of defense More specific (adaptive) and powerful than innate Major components: Lymphocytes Lymphocyte products Two types of adaptive immunity: Humoral immunity (mediated by antibodies) Cellular immunity (mediated by T cells)

Immunology Overview Definitions Cells Lymphocytes Antigen-presenting cells Effector cells

Lymphocytes Present in lymphoid organs and in blood Groups T-lymphocytes (grow up in thymus) B-lymphocytes (grow up in bone marrow) Each one has receptors for a specific antigen Recognize millions of different antigens! Diversity generated by: rearrangement of antigen receptor genes different joining of the gene segments Gene rearrangement studies

Lymphocyte (could be B cell or T cell!)

T Lymphocytes Two basic functions: Kill stuff (cytotoxic T cells) Help other cells do their jobs (helper T cells) T-cell receptor (TCR) complex recognizes antigens Binds antigen Sends signals to the T cell Antigens must be: Displayed by other cells… …AND bound to an MHC receptor

The T-Cell Receptor Bound to Antigen Antigen-presenting cell T cell

Cytotoxic T cells surrounding tumor cell

Major Histocompatibility Complex (MHC) class II MHC genes class III MHC genes class I MHC genes Class II MHC molecule Class I MHC molecule

Class I and II MHC Molecules Class I molecules Display antigens from within the cell (e.g., viral antigens) to CD8+ T cells. Present on all nucleated cells! (Good idea.) Class II molecules Display extracellular antigens (e.g., bacterial antigens the cell has eaten) to CD4+ T cells Present mainly on antigen presenting cells, like macrophages! (Makes sense.)

B Lymphocytes Basic function: make antibodies B-cell receptor complex recognizes antigens Binds antigen Sends signals to B cells Antigens can be free and circulating (don’t have to be bound to MHCs or displayed by other cells to be recognized!)

Natural Killer (NK) Cells Belong to innate immunity arm Receptors not highly variable (like T and B cell receptors) Main job: recognize and kill damaged or infected cells

Natural killer cell

Natural killer cell (top) killing infected cell (bottom)

Immunology Overview Definitions Cells Lymphocytes Antigen-presenting cells

Antigen-Presenting Cells Main job: catch antigens and display them to lymphocytes Dendritic cells Have fine cytoplasmic projections Present all over body: skin, lymph nodes, organs Capture bug antigens, display to B and T cells Macrophages Macrophages also eat bugs and present antigens to and T cells Their role in activating the adaptive system is not as pivotal though!

Dendritic cell surrounded by lymphocytes

Dendritic cell (right) talking to lymphocyte (left)

Monocyte Macrophage

Macrophage reaching for bacterium

Macrophage gorging on bacteria

Immunology Overview Definitions Cells Lymphocytes Antigen-presenting cells Effector cells

Effector Cells These guys carry out the ultimate immune system task: eliminate infection Types of effector cells NK cells Plasma cells T cells (both CD4+ and CD8+) Macrophages Other leukocytes (e.g., neutrophils)

Immunology Overview Definitions Cells Lymphocytes Antigen-presenting cells Effector cells Responses The innate immune response Capturing and displaying antigens Cell-mediated immunity Humoral immunity Immunologic memory

Immunology Overview Definitions Cells Lymphocytes Antigen-presenting cells Effector cells Responses The innate immune response

The Innate Immune Response Main bug barriers: skin, mucosa If bugs make it through epithelium, they encounter innate immune system What happens in the innate immune system? Phagocytes eat bugs, kill them Cytokines are released Complement is activated The adaptive immune system is activated

Immunology Overview Definitions Cells Lymphocytes Antigen-presenting cells Effector cells Responses The innate immune response Capturing and displaying antigens

Capturing and Displaying Antigens Dendritic cells in epithelium capture bug antigens, transport them to lymph nodes Dendritic cells display antigens (using their MHC receptors) to T cells B cells in lymph nodes also recognize antigens Antigens and molecules produced during innate immune response trigger proliferation and differentiation of B and T cells

Immunology Overview Definitions Cells Lymphocytes Antigen-presenting cells Effector cells Responses The innate immune response Capturing and displaying antigens Cell-mediated immunity

Cell-Mediated Immunity Humoral Immunity Cell-Mediated Immunity

Cell-Mediated Immunity Humoral Immunity Cell-Mediated Immunity

Naïve T Cells Turn Into Effector T Cells Naïve T cells are activated by antigen and costimulators in lymph nodes… …then they proliferate and differentiate into effector cells that go find the antigen. CD4+ T cells help macrophages eat bugs CD8+ T cells kill infected cells directly All these steps are dependent upon cytokines

What are cytokines? Polypeptides that do lots of different things: Help leukocytes grow and differentiate Activate T cells, B cells and macrophages Help leukocytes communicate Recruit neutrophils Made by lymphocytes and macrophages Examples: tumor necrosis factor (TNF), interleukins, interferons

Types of Effector T Cells CD4+ T cells differentiate helper T cells These guys go to the site of infection and help other cells do their thing. CD8+ T cells differentiate into cytotoxic T cells These guys kill cells that have microbes in their cytoplasm. They are like little assassins.

Matt Damon and the “asset”

Cell-Mediated Immunity

Immunology Overview Definitions Cells Lymphocytes Antigen-presenting cells Effector cells Responses The innate immune response Capturing and displaying antigens Cell-mediated immunity Humoral immunity

Cell-Mediated Immunity Humoral Immunity Cell-Mediated Immunity

Humoral Immunity B cells are activated by exposure to antigens (sometimes with the help of CD4+ T cells) B cells differentiate into plasma cells (which make antibodies) The antibodies do nasty things to bugs

What is an antibody? Y-shaped glycoprotein 2 light chains (κ or λ) 2 heavy chains (α, γ, δ, ε, or μ) Constant regions of heavy chain form Fc fragment Binds to APCs Defines isotype (Ig class: IgA, IgE, etc.) Variable regions of both chains form Fab fragments Binds to antigen Defines idiotype

What do antibodies do? Bind to – and “neutralize” – bugs, so they can’t infect cells. Coat (“opsonize”) bugs, making them yummy to macrophages and neutrophils (which have receptors for the Fc portion of IgG! How handy!). Activate complement.

What is complement? Just give me the bottom line. It’s a bunch of proteins that poke holes in cells.

Okay, give me a little more information. Consists of about 20 plasma proteins (C1, C2, etc.) Can be activated in a few different ways Activation proceeds in a cascade fashion End results: Cell lysis Chemotaxis Opsonization

Complement, ridiculously oversimplified

Immunology Overview Definitions Cells Lymphocytes Antigen-presenting cells Effector cells Responses The innate immune response Capturing and displaying antigens Cell-mediated immunity Humoral immunity Immunologic memory

Immunologic Memory Most effector lymphocytes die after killing the bug. A few memory cells live on for years. Expanded pool of antigen-specific lymphocytes Respond faster, better than naïve cells Vaccines depend on these guys

Summary of the Adaptive Immune Response

Immunology Overview Definitions Cells Lymphocytes Antigen-presenting cells Effector cells Responses The innate immune response Capturing and displaying antigens Cell-mediated immunity Humoral immunity Immunologic memory