MIC301/MIC303/320 lecture 6 2014 1

INTRODUCTORY IMMUNOLOGY MIC 301/320: Block 3

SPRING 2014Lecture 6 = The Last

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Take a Deep Breath

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Antigen Recognition by B-cells and T-cells is Distinct (“native” vs. a “little bit of antigen and a

little bit of MHC”)

MIC301/MIC303/320 lecture 6 2014

Antigen Chipping is Needed for T-cell Recognition and Activation

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Who is shredding and presenting?

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Eco-Shredder

Professional Shredder

all healthy cells

professional Ag

presenting cells:

DC>MF>B-cell

only

MHC

cla

ss I

MHC

I AN

D M

HC II

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Antigen Capture by Antigen Presenting Cells and Their Activation of Th cells Determines the Specifics of the Adaptive Immune Response

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How does CTL activation really work? (Menage a Trois)

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MHC I–CD8/TCR+ costimulation

cytokine

MHC II–CD4/TCR+ costimulation

no costimulation for effector function!!!

How does B-cell activation really work?

(Menage a deux)

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Definitions (20)MHC molecules have two functions. They are essential for the adaptive immune system because they “display” peptides of an antigen for their recognition by T-cells. Human MHC is also known as HLA. But they were discovered and named as genetic loci that are the principal determinants of acceptance or rejection of tissue grafts between individuals. Individuals that are identical at their MHC loci will accept grafts. There are 3 biallelicly expressed class I and, respectively, class II genes.

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(1) How can MHC molecules accommodate an unlimited number of

antigens ?

note that only ~3-4 anchor residues of the “chipped” antigen need to fit with a given MHC grooveMIC301/MIC303/320 lecture 6 2014 10

(2a) How can MHC accommodate an unlimited number of antigens ?

o three different types of molecules (A, B and C) are on each cell

o both alleles for each of the three types are coexpressed

o expressed by all “healthy” cells

o one individual has the same combination of HLAs on all cells

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(2b) How can MHC accommodate an unlimited number of antigens ?

o three different combinations of dimers (α + β) are on each cell

o both alleles for each of the three types are coexpressed

o one individual has the same combination dimers on all of his antigen presenting cells

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Definitions (21)

Polymorphisms indicates that genes exist in a variety of versions (different alleles) each of which is present in a different individual. MHC/HLA comprises the most polymorphic gene cluster in humans. All alleles are inherited.

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Why has MHC Polymorphism Evolved?

Survival of Mankind

a threatening pathogene

population

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interacts with CD8 interacts with CD4

presents intracellular antigens or cell remnants

presents extracellular antigens

expressed by all cellsexpressed by antigen-

presenting cells (DC, B, macrophage

3x2 and 6x2 different gene loci for MHC I and, respectively, MHC II in each individual can accommodate an many distinct peptides

Summary of MHC features responsible for antigen presentation

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Discovery of MHC and its Polymorphism as an Antigen that is

Specific for Each Individual

??

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Differences of MHC, TCR and BCR/Abfunction MHC I MHC II TCR BCR/Abdisplay peptide peptide no no

recognition no no peptide +MHC

part ofnative protein

specialbinds also to

CD8(T cell kill)

binds also toCD4

(T cell help)

always receptor

receptor and secreted effector

molecules on single cell

3 x 2 distinct alleles

3 x 2 distinct allelic pairs

single species unique

single speciesunique

variability in single human

3 distinctpolymorphic

genes

6 distinct polymorphic

genes

diversity >1016

diversity >1x1011

generated by inheritance inheritance recombination recombination

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Superantigens overpower the immune system (bind to a common region of MHC II

and to 5-30% of all TCRs

Take a Deep Breath

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Vaccination and the Immune System (a)

active vaccinatio

n

immunity

functional immune system

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Definitions (22)

Adjuvant is a substance, distinct from the antigen or a pathogens, that promotes the accumulation and activation of antigen-presenting cells at the site of antigen exposure. It acts as the “danger” signal that TLRs promote. It is the “little dirty secret of immunology.”

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APCs “translate” that antigens are dangerous (rather than harmless self) because their danger signals

induce costimulation

coactivation

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Vaccination and the Immune System (b)

active vaccinatio

n

dysfunctional immune system

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Vaccination and the Immune System (c)

passive vaccinatio

n

dysfunctional immune system

temporarily

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Active versus passive vaccination

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Two Principles of Hypersensitivity

autoantigen

allergy

autoimmunity

foreign but harmless antigen

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Possibilities for dealing with “autoimmune” lymphocytes

autoimmune cells suicide during development

(clonal deletion)

1

unable to activate if there is no

“danger” or if there is no signal 2

(anergy)

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negative function (regulatory T-cells)

3

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Clonal deletion = Negative selection = Central tolerance

B-cells: Bone

marrow T-cells: Thymus

1

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Induction of Anergy

2

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Development of regulatory T-cells (TRegs)

3

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Blocking Tregs Strongly Activate the Immune System

“It took the past two decades for researchers to identify the braking mechanism, a molecule called CTLA-4, and develop a compound that gets the immune system to lift its foot off this brake enough to sufficiently attack melanoma, said James Allison, chairman of Memorial Sloan-Kettering Cancer Center's immunology program, whose research on the CTLA-4 molecule's role paved the way for ipilimumab's development.”

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Definitions (23)

Tolerance is the normal ability of the immune system to prevent self-destruction = autoimmune diseases. It is achieved by clonal deletion (thymus, bone marrow), generation of regulatory T-cells (thymus) and the induction of anergy (periphery). Large tumors can exploit regulatory T-cells and anergy against tumor antigens for their own good.

fore

ign

dang

ero

us

antig

ens

self

antig

ens

or

harm

less

an

tigen

s

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Desired versus UndesiredAdaptive Immune Responses

reaction

no reactionMIC301/MIC303/320 lecture 6 2014

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Molecules and Cells Causing of Hypersensitivity Reactions

antibodies T-cells

time until onset

other than IgE

IgGcomplex

es

usually allergy usually

autoimmunity

example 1example 2

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Type IV Hypersensitivity is mediated by T-cells

Examples:Type I diabetesRheumatoid arthritisInflammatory bowel diseases

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Differences in the Fc region of the Abs (same specificity but different “isotype”) promote

unique functions

}Fc regiondi

ffere

nt e

ffect

or fu

nctio

ns

o Complement activation (IgM)

o Phagocyte receptor binding = opsonizing (IgG and IgE)

o Localisation in body (placenta crossing = neonatal immunity (IgG), breast milk, gut and respiratory tract IgA)

o Mastcell receptor binding (IgE)

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Definitions (24)The isotype of an antibody is determined by

its constant region. B-cells can change their isotype in an ordered sequence during an immune response (but not their specificity). Isotypes can switch orderly from IgM to IgG to IgA and, finally, to IgE. This does not change the specificity of the antibody but it effects its function including its biological distribution, its interaction with complement and its binding to different Fc receptors. Thus antibodies have two biologically critical regions: The specific antigen recognition site and the Fc-region of their isotype shared with different specific antibodies.

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Type I hypersensitivity

(immediate)

http://upload.wikimedia.org/wikipedia/commons/c/ce/Mast_cells.jpg

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Any Questions?I will be outside the lecture room after

packing up