Microbiology 204: Cellular and Molecular Immunology

Class meets MWF 11-12:30

Lectures are open to auditors

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

Textbook recommended: Janeway et al Immunobiology or Abbas and Lichtman Cellular and Molecular Immunology

Microbiology 204: Cellular and Molecular Immunology

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

My office hours: Mondays 4-5PM HSE1001F (defranco@cgl.ucsf.edu)

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

• Lymphocytes– Mediators of adaptive immune responses; only

cells with specific receptors for antigens• 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• Effector cells– Function to eliminate microbes; include

lymphocytes, granulocytes (neutrophils, eosinophils), macrophages

Cells of the myeloid lineages

Innate vs. Adaptive Immunity

Innate Immune component Recognition Property Function

Toll-like receptors Cell wall components;Nucleic acids

Trigger inflammationPromote adaptive response

Collectins Carbohydrate structures Agglutination, phagocytosis,complement activation

Alternative pathway ofcomplement

Membranes lacking proteinsthat block it

Damage to cells; promotephagocytosis

Apoptotic sensors withincells (p53, etc.)

Stress within cell,unscheduled DNA replic.Presence of dsRNA

Killing of virus-infected cell

Examples of Innate Immune Recognition

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

Pathogen recognition by adaptive immunity: great

variety, selectivity

Great variability of antigen recognition is created by

combination of gene segments during lymphocyte development

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

Two types of MHC

Coordination of properties with functions of two types of T cells: source of peptide and cells expressing

Two types of T cells: coordination of function with properties of antigen-

presentation

CD4 T cells .Help other immune cellsRecognize peptide + MHC IIMHC II is expressed primarily on immune cellsPeptides are from endocytosed antigen

CD8 T cells .Kill virus-infected cellsRecognize peptide + MHC IMHC I is expressed on all nucleated cellsPeptides are from cytosolic antigen

Generation of lymphocytes of many specificies

Clonal deletion to remove self-reactive lymphocytes

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

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

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.

Sequence of Events in an Immune response

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)

Immune responses often can be characterized as type 1 or type 2

• Type 1 immune responses: Killing microbes– Pro-inflammatory;

neutrophils and macrophages

– Antibody classes involved in phagocytosis and complement activ.

– Macrophage activation

• Type 2 immune responses: Defense at epithelium– Allergic

inflammation: eosinophils, basophils

– Antibody classes: IgE and IgG1 (mast cell activation)

– Expulsion type reactions (diarrhea, coughing, sneezing, etc.).

Congenital immunodeficiency diseases are often caused by blocks at different stages of lymphocyte maturation

LYMPHOCYTE DEVELOPMENT

The Immunoglobulin Superfamily(a few examples)

Integrins: Regulated Cell-cell and cell- ECM adhesion

Cytokine receptor families

Chemokines: lymphoid or homeostatic chemokines