Cellular and Molecular Immunology.ppt

Microbiology 204: Cellular and Molecular Immunology

Class meets MWF 1:00-2:30PMLectures are open to auditors

Discussions are restricted to those enrolled in class (or by permission)

Problem sets and review sessions every other week by our TA: Betsy Gray ([email protected])

Course web site:http://immunology.ucsf.edu/immuno/courses/micro204/index.html

Recommended textbook : Janeway et al Immunobiology;OR Abbas and Lichtman Cellular and Molecular Immunology; OR DeFranco, Robertson, and Locksley Immunity

Microbiology 204: Cellular and Molecular Immunology

Grades: 2/3 take-home final and 1/3 participation in discussions

My office hours: Mondays 3-4PM HSE1001F or by arrangement ([email protected])

The central questions

• How does the immune system respond to different infections?

• Why does the immune system not respond to self antigens?

• What are the pathogenic mechanisms and pathologic consequences of abnormalities in the immune system?

The central questions

• How does the immune system respond to different infections?– Microbes are recognized by two mechanisms, evolved

broad recognition mechanisms (innate immunity), and by highly specific lymphocyte antibodies and T cell receptors (adaptive immunity)

– Different types of microbes are eliminated by different effector mechanisms, which are designed to best combat each type of microbe

• Why does the immune system not respond to self antigens?

• What are the pathogenic mechanisms and clinico-pathologic consequences of abnormalities in the immune system?

Cells of the immune system• Sentinel cells of tissues

– Immature dendritic cells, macrophages, mast cells: recognize infection or antigen and induce inflammation, activation of lymphocytes

• Antigen-presenting cells (APCs)– Specialized to capture, concentrate, and display antigens for

recognition by lymphocytes– Dendritic cells; macrophages, B cells; follicular dendritic

cells– Different APCs serve different roles in adaptive immune

responses• Lymphocytes

– Mediators of adaptive immune responses; only cells with specific receptors for antigens

• Effector cells– Function to eliminate microbes; include lymphocytes,

granulocytes (neutrophils, eosinophils), macrophages

Cells of the myeloid lineages

Sentinel immune cells are equipped with innate immune receptors

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TLR recognition

leads to production of inducers of

inflammation

TNF

© New Science Press Ltd. 2000

or dendritic cell

Inflammatory mediators:proteins and lipids

Others

Cytokines

•“Cytokines” are soluble protein mediators secreted by immune cells (mostly) that act on other cells to regulate their activity; many are called “interleukins” (IL-1, IL-2, etc.)

•Cytokines have many functions, we’ll focus on a few central functions of a few key cytokines

•A subfamily of cytokines primarily functions in directing migration of cells, these are called “chemotactic cytokines” or “chemokines”

Cytokines and Inflammation

• Macrophages or DCs stimulated via TLRs make pro-inflammatory cytokines, especially TNF (Tumor necrosis factor), IL-1, and IL-6

• TNF and IL-1 signal to endothelial cells to make them:– Leaky to fluid (influx of plasma; containing

antibodies, complement components, etc.)– Sticky for leukocytes, leading to influx of

neutrophils first, then monocytes, lymphocytes• IL-6 promotes adaptive immune responses and has

systemic effects

Cytokine receptor families

Leukocyte recruitment to sites of inflammation


or DC

Innate vs. Adaptive Immunity

Anatomy of the lymphoid system

Anatomy of a lymph node

Naïve lymphocytes circulate between blood and lymphoid tissues; antigen in tissue arrives at draining lymph node via lymph flow and being carried by dendritic cells

Dendritic cells pick up antigen in the tissues





Dendritic cells take up antigen and mature


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Innate signalcytokine

Dendritic cells can take antigen to the draining lymph node to activate

T cells



Generation of lymphocytes of many specificities

Clonal deletion to remove self-reactive lymphocytes

Clonal selection to expand pathogen-reactive lymphocytes during an immune response

The Clonal Selection Hypothesis

Stages of lymphocyte activation

• Naïve lymphocytes– Mature lymphocytes that have not previously encountered

antigen; function -- antigen recognition– Preferential migration to peripheral lymphoid organs (lymph

nodes), the sites where immune responses start

• Effector lymphocytes– Activated lymphocytes capable of performing the functions

required to eliminate microbes (‘effector functions”)– Effector T lymphocytes: cytokine secretion (helper cells),

killing of infected cells (CTLs)– B lymphocytes: antibody-secreting cells (e.g. plasma cells)

• Memory lymphocytes– Long-lived, functionally silent cells; mount rapid responses

to antigen challenge (recall, or secondary, responses)

Pathogen recognition by adaptive immunity: great

variety, selectivity

Great variability of antigen recognition is created by

combination of gene segments during lymphocyte development

Antibodies are protective in multiple ways





neutralization

Monoclonal antibodies used in medicine

Standardized, unlimited reagents for diagnosis or therapy (human antibodies or “humanized” antibodies can be made)


Two types of T cells

CD Nomenclature

• Structurally defined leukocyte surface molecule that is expressed on cells of a particular lineage (“differentiation”) and recognized by a group (“cluster”) of monoclonal antibodies is called a member of a cluster of differentiation (CD)

• CD molecules (CD antigens, CD markers) are:• Identified by numbers• Used to classify leukocytes into functionally

distinct subpopulations, e.g. helper T cells are CD4+CD8-, CTLs are CD8+CD4-

• Often involved in leukocyte functions• Antibodies against various CD molecules are used to:

• Identify and isolate leukocyte subpopulations• Study functions of leukocytes• Eliminate particular cell populations

Use of monoclonal antibodies recognizing CD antigens by flow

cytometry

Flow cytometry: measure the amount of a protein on the surface (or inside) individual cells; measure the numbers of particular types of cells in blood (etc.)



Coreceptors CD4 and CD8 keep T cells focused on MHC-presented

antigen

Helper T cells can adopt different fates

with different functions

Cytokines drive an antigen-activated naïve CD4 T cell toward one or another of these types (can be from helper T cells or from innate immune cells)



Principal mechanisms of defense against microbes

Antibodies Phagocytes T cells (CTLs) (may work with antibodies, T cells)

All microbes

All microbes

Intracellular microbes, esp.

viruses

Self-reactive lymphocytes may be purged during development or in the periphery

Applies to B cells and T cellsFor T cells: costimulatory molecules include B7-1 and B7-2 on dendritic cells

Mechanism for directing the immune response against microbes and not against self, food, etc.

Technology

Cellular and Molecular Immunology.ppt