Lecture 4Lecture 4Activation of Adaptive ImmunityActivation of Adaptive Immunity

OverviewOverview

In order to initiate an immune response antigen In order to initiate an immune response antigen must be must be recognizedrecognized..

Antigen recognition depends on detection of Antigen recognition depends on detection of antigen by special antigen by special receptorsreceptors..

Antigen recognition depends on cellular Antigen recognition depends on cellular cooperationcooperation..

Cellular cooperation is controlled by recognition Cellular cooperation is controlled by recognition of of MHCMHC-encoded receptors.-encoded receptors.

Clonal Selection Clonal Selection TheoryTheory

(F. Macfarlane Burnet)(F. Macfarlane Burnet) Pre-existence of of many different Pre-existence of of many different

potentialpotential antibody producing cells antibody producing cells Each cell displays surface Each cell displays surface receptorsreceptors for for

specificspecific antigens antigens Antigen encounter Antigen encounter selectsselects cells cells

Postulates of the Clonal Postulates of the Clonal Selection HypothesisSelection Hypothesis

Each lymphocyte bears a single type of receptor of a Each lymphocyte bears a single type of receptor of a unique unique specificityspecificity

Interaction between a foreign molecule and a lymphocyte Interaction between a foreign molecule and a lymphocyte receptor capable of binding that molecule with high affinity receptor capable of binding that molecule with high affinity leads to leads to lymphocyte activationlymphocyte activation

The differentiated The differentiated effectoreffector cells derived from an activated cells derived from an activated lymphocyte will bear receptors of lymphocyte will bear receptors of identical specificityidentical specificity to those to those of the parental cell from which that lymphocyte was derivedof the parental cell from which that lymphocyte was derived

Lymphocytes bearing receptors specific for self molecules are Lymphocytes bearing receptors specific for self molecules are deleteddeleted at an early stage in lymphocyte development and are at an early stage in lymphocyte development and are therefore absent from the repertoiretherefore absent from the repertoire

First a Word About “Cluster of First a Word About “Cluster of Differentiation/Designation” (CD) Differentiation/Designation” (CD)

AntigensAntigens What are they?What are they?

Differentiation antigensDifferentiation antigens Expressed by cells at distinct stages of Expressed by cells at distinct stages of

differentiationdifferentiation Expressed by cells having different Expressed by cells having different

functionsfunctions How are they detected?How are they detected?

Fluorescence-Activated Cell Sorting Fluorescence-Activated Cell Sorting (FACS)(FACS)

Major Lymphocyte PopulationsMajor Lymphocyte Populations

B lymphocytes and plasma B lymphocytes and plasma cellscells

T lymphocytesT lymphocytes Helper/Inducer (CD4)Helper/Inducer (CD4) Suppressor (CD8)Suppressor (CD8)

T Cell Recognition of AntigenT Cell Recognition of Antigen Recognize antigen Recognize antigen peptide fragmentspeptide fragments bound to bound to

specialize cell surface molecules on antigen-specialize cell surface molecules on antigen-presenting cells (APC).presenting cells (APC).

Molecules are encoded by major histocompatibility Molecules are encoded by major histocompatibility complexcomplex

Peptides are displayed to T cells as Peptides are displayed to T cells as peptide:MHC peptide:MHC complexescomplexes

T cell antigen receptors T cell antigen receptors recognizerecognize peptide:MHC peptide:MHC complexescomplexes

Each MHC molecule can bind Each MHC molecule can bind numerousnumerous different different peptidespeptides

Two classesTwo classes of MHC molecules of MHC molecules

Major Histocompatibility Major Histocompatibility Complex (MHC) Gene Complex (MHC) Gene

ProductsProducts Class IClass I

Antigen is usually Antigen is usually endogenousendogenous (e.g. viral proteins). (e.g. viral proteins). CD8CD8++ cytotoxic T lymphocytes (CTLs) recognize cytotoxic T lymphocytes (CTLs) recognize

antigen in association with class I MHC gene antigen in association with class I MHC gene product on APC.product on APC.

Class II MoleculesClass II Molecules Antigen is usually Antigen is usually extracellularextracellular.. CD4CD4++ Helper T Lymphocytes recognize antigen in Helper T Lymphocytes recognize antigen in

association with class II MHC gene product on APC.association with class II MHC gene product on APC.

Cellular Cooperation and Cellular Cooperation and Antigen RecognitionAntigen Recognition

APCAPC ExtracellularExtracellularAntigenAntigen

CD4CD4++ Helper T Helper T LymphocyteLymphocyte

Class II Class II MHC-MHC-associatedassociatedantigenantigen

++

B Cell Antigen RecognitionB Cell Antigen Recognition

Cell surface Cell surface immunoglobulin receptor immunoglobulin receptor or B-or B-cell receptor (IgM and IgD)cell receptor (IgM and IgD)

Antigen Antigen contactcontact initiates B-cell activation, initiates B-cell activation, clonal expansion, maturation to plasma clonal expansion, maturation to plasma cellcell

Antigen receptor is Antigen receptor is identicalidentical to to immunoglobulin that will ultimately be immunoglobulin that will ultimately be producedproduced

Antigen Presenting CellsAntigen Presenting Cells

Macrophages/monocytesMacrophages/monocytes Dendritic cells (e.g., Langerhan’s cells)Dendritic cells (e.g., Langerhan’s cells) B cellsB cells

Properties Properties of Antigen-of Antigen-Presenting Presenting

CellsCells

Cellular Cellular CooperationCooperation

T H B antigenantigen

Antibody secretion Antibody secretion by plasma cellsby plasma cells

Plasma CellsPlasma Cells

Antigen presenting cellAntigen presenting cell

Antigen presentation to T Antigen presentation to T and B cells by APCand B cells by APC

T cells elaborate T cells elaborate cytokinescytokines to facilitate B to facilitate B cell proliferation and cell proliferation and maturationmaturation

AdjuvantsAdjuvants

Freund's Complete Adjuvant (Water-in-oil emulsion)Freund's Complete Adjuvant (Water-in-oil emulsion) mineral oilmineral oil emulsifying agentemulsifying agent microbial preparation (eg. heat-killed extract of microbial preparation (eg. heat-killed extract of

Mycobacterium tuberculosisMycobacterium tuberculosis)) aqueous phase containing antigenaqueous phase containing antigen

Aluminum Hydroxide GelAluminum Hydroxide Gel Microbial AdjuvantsMicrobial Adjuvants

C. parvumC. parvum BCGBCG

Peptides and Synthetic PolymersPeptides and Synthetic Polymers

Effector MechanismsEffector Mechanisms Mechanisms that are used by the immune system Mechanisms that are used by the immune system

to eliminate pathogens (or other substances) to eliminate pathogens (or other substances) from the bodyfrom the body

Cellular effector mechanismsCellular effector mechanisms Activated T cellsActivated T cells Natural killer cellsNatural killer cells

Humoral effector mechanisms (antibody)Humoral effector mechanisms (antibody) NeutralizationNeutralization OpsonizationOpsonization Complement activationComplement activation Antibody-dependent cell-mediated cytotoxicity (ADCC)Antibody-dependent cell-mediated cytotoxicity (ADCC)

Effector Activity Against Effector Activity Against PathogensPathogens

Clonal Expansion Following Antigen Clonal Expansion Following Antigen Exposure Exposure

Virgin lymphocyte pool Virgin lymphocyte pool

PRIMARY RESPONSE PRIMARY RESPONSE

SECONDARY RESPONSESECONDARY RESPONSE

effector cells effector cells memory cell pool memory cell pool

effector cells effector cells memory cell pool memory cell pool

The Bottom LineThe Bottom Line In order to initiate an immune response In order to initiate an immune response

antigen must be antigen must be recognizedrecognized.. Antigen recognition depends on detection Antigen recognition depends on detection

of antigen by special of antigen by special receptorsreceptors.. Antigen recognition depends on Antigen recognition depends on cellular cellular

cooperationcooperation.. Cellular cooperation is controlled by Cellular cooperation is controlled by

recognition of recognition of MHCMHC-encoded receptors.-encoded receptors. Antigen “drives” the process resulting in Antigen “drives” the process resulting in

““effectoreffector” cells and “” cells and “memorymemory” cells.” cells.