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