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 (elizabeth.gray@ucsf.edu)

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 (anthony.defranco@ucsf.edu)

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

© New Science Press Ltd. 2004

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

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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

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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

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neutralization

Monoclonal antibodies used in medicine

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

© New Science Press Ltd. 2003

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.)

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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)

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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.