Lecture 2: Adaptive Immunity

Which cells are involved in adaptive immunity

Natural killer cell

T cell/ B cell (lymphocytes) → effector T cells and plasma cells

Which ones are phagocytes

Macrophages, Neutrophils, Dendritic cells (monocytes too technically)

Innate immunity

Provides routine protection

Eg, pattern recognition receptors

Adaptive immunity

Develops throughout life

Antigens, antibodies, etc

… cause response

Antigens (foreign substance)

System produces … to bind to antigens

Antibodies

Adaptive immunity takes a week or more to build following first exposure, what must protect during this time

Innate immunity

(Person may not survive long enough)

Adaptive immunity has …

Memory

(Stronger response to re-exposure)

… relies upon this ability to have memory/ have stronger response to reexposure

Vaccination

Response of adaptive immunity has molecular …

Specificity

(Specific to certain molecules on certain microbes)

Must … between ‘healthy self’ and dangerous particles (pathogens)

Distinguish

Two responses of adaptive immunity

Primary response

Secondary response

Primary response

First response to antigen

Secondary response

Second encounter with antigen

Stronger than primary response

Why are the two responses linked

Adaptive immune system ‘remembers’ mechanism that proved effective against that specific antigen during primary response

Two basic strategies for countering foreign materials

Humoral immunity

Cell-mediated immunity (CMI)/ cellular immunity

Humoral immunity

Works to eliminate extracellular antigens (Bacteria, toxins, viruses in bloodstream, tissue fluids)

Cell-mediated immunity (CMI) or cellular immunity

Deals with antigens residing within a host cell

(Ex invading virus infecting cell)

Dendritic cells

‘Scouts’

They bring antigens to the adaptive immune cells

B cells/ T cells are initially …

Naive (they are inactive)

What happens once B/ T cells are activated

They proliferate into their active forms Th and Tc cells

Some differentiate and some become memory cells

Roles of Th cells

Increase killing power of macrophages

Can also activate B cells

Role of Tc cells

Trigger apoptosis of infected cells

Role of B cells

Trigger production of plasma cells which produces Y-shaped antibodies

Adaptive immunity - Humoral

Outside cells

Adaptive immunity - cell-mediated

Inside cells

B cells and T cells have … receptors

Membrane-bound receptors

B cell Receptors (BCR)

Correspond to antibodies the B cell is programmed to make

T cell Receptor (TCR)

Recognize ‘presented’ antigens

What gives difference to helper vs cytotoxic T cells

CD marker (surface protein)

How do T and B cells move around

Via lymphatic system

(Must interact with specific antigens)

Each B and T cells is specific to only one or few antigens… have to move around

Primary lymphoid organs

Thymus and bone marrow

Secondary lymphoid organs

Lymph nodes, spleen, tonsils

Where do naive T and B cells gather

Lymph nodes (Scattered throughout)

Lymphatic vessels

Also helps bring antigen to B and T cells

Some fluid from circulatory system and tissues enters lymphatic vessels (becomes lymph fluid)

Brings antigens (from tissues) to areas where immune cells are concentration (at lymph nodes)

Lymph nodes

Where lymphocytes gather to contact antigens

Peyer’s patches

Allows sampling of intestinal contents via specialized M cells and dendritic cells

(T and B cells gather here)

Where do all blood cells arise

In bone marrow

Where do B cells mature

In bone marrow

Where do T cells mature

Migrate to thymus and mature there

Where do mature B and T cells gather

At secondary lymphoid organs and await antigen encounter

Antigens

‘Antibody generator’

Any molecule that reacts specifically with a Y-shaped antibody, a B cell receptor, or a T cell receptor (Elicit immune response)

Enormous variety of antigens (microbes, pollen, etc)

Two general categories of antigens

T dependent antigens (most)

T independent antigens

T-dependent antigens

B cells depend on Th cell to activate

T-independent antigens

B cells independently activate without Th cell’s help

(Eg lipopolysaccharide and molecules with repeating subunits such as carbohydrates)

Antigens are … the whole organism

NOT

Part of the organism recognized by antibodies

Epitopes (aka antigenic determinants)

• regions of macromolecules (10 or so amino acids; 3D shapes)

• Bacteria carry many different epitopes

• Can be on cell surface or on cell structures

Antibodies are also called

Immunoglobulins

Antibody structure

Y shaped proteins with two general parts

• Two identical arms (Fab regions)

• Stem (Fc region)

Which part of the antibody binds antigen

Fab region (ab → antigen binding)

Which part of the antibody ‘red flag’ tags antigen

Fc region (stem)

Ends of Fab

Binds to antigen and is variable + gives specificity

Free and Fc (if not bond)

Constant so cells can recognize tag

How do antibodies protect directly

Bind and prevent attachment of antigen to host cell

(No host cell gets involved)

How do antibodies protect indirectly

Tag antigen for elimination (host still does job)

What kind of protection is neutralization

Direct

• covers object - can’t attach to host

What kind of protection is opsonization

Indirect

• antibodies coat antigen, cell eats (phagocyte)

What kind of protection is complement system activation

Indirect

• Complement system protein attaches to antigen which signal opsonization by C3b, inflammatory response, lysis of foreign cells

What kind of protection is immobilization and prevention of adherence

Direct

• Antibody binds to flagellum of antigen which prevents adherence

What kind of protection is cross linking

Direct or could be indirect

Different arms of antibody attach to different antigens to immobilize and bring together

What kind of protection is Antibody-Dependent Cellular Cytotoxicity (ADCC)

Indirect

Antibodies cover infected ‘self’ cell and natural killer cell kills cell

Classes of Antibodies/ Immunoglobulin

Five major classes

Each has different constant region of heavy chain

Some form of multimers (Y-shape comes together)

Each has distinct function and properties

Not all same percentage in serum (blood)

Differ in half-lives

How do lymphocytes multiply

Clonal selection theory

• Billions of different B and T cells present

• Each interacts with a single epitope (of antigen)

• Diversity of antigen recognition is random

• Lymphocytes in secondary lymphoid organs wait their ‘dream antigen’

• Once activated they multiply clonally (they are identical/ clones)

B-cell activation

Antigen presentation

To become activated and divide, need to present antigen to helper T cells for ‘confirmation of danger’

Steps for B-Cell

1. Bind antigen

2. Internalize antigen (endocytosis)

3. Degrade into peptides

4. Present peptides to Th cells via MHC class II molecules

What are the MHC class II molecules called

Major histocompatibility complex (MHC) molecules

This initial B cell activation is part of the … of humoral immunity

Primary response

• takes 10-14 days for substantial antibodies to accumulate

What do B cells do as infection progresses

Some activated/ memory B cells continue generating antibodies and the concentration (titer) increases over time of the immunoglobins (Ig)

In the case of resolved infection, additional exposure to the antigen later on yields

A much faster secondary respon se

Affinity maturation

Activated B cells can also gain mutations that make them bind antigens longer, and these will proliferate more (via natural selection)

Characteristics of Secondary Response

Significantly faster, more effective response

• Pathogens usually eliminated before causing harm

• Vaccination exploits this natural phenomenon

Memory B cells are responsible

• greater number present after first response

• Their receptors already fine tuned

• When activated, some quickly become plasma cells, produce antibodies

T cell activation/ response

Play different role than B cells

Never produce antibodies

Effector T cells directly interact with target cells (self cells, macrophages, B cells)

• cause distinct changes in target cells

Have T-cell receptors (TCR) that interact with antigens presented by by another cell

Where are the antigens presented to T cells held

In major histocompatibility complex molecules

Two types of MHC molecules

MHC class I

MHC class II

MHC class I

Presents endogenous antigens (those inside cell)

• all nucleated cells make

MHC class II

Present exogenous antigens (originating outside cell)

• produced by dendritic cells, B cells, macrophages

Cytotoxic T cells recognize antigens on

MHCI

Helper T cells recognize antigens on

MCHII

How do we decipher between the two T-cells

Cluster of differentiation (CD) markers

(Tc cells usually have CD8, Th cells usually have CD4)

(CD4 is a receptor for HIV, which infects Th cells)

How do dendritic cells play critical role in activation of T cells

Reside in peripheral tissue (skin, mucosa), Peyer’s patch

Have Toll-like receptors to recognize pathogens

Sense and signal danger

Present antigens on both MHC I and MHC II

What do dendritic cells produce if they sense danger

Co-stimulating molecules that signal danger

Functions of activated cytotoxic T cells (Tc)

Have learned what ‘danger’ is, seek out MHC I molecules (self cells) with antigen matches

If binds, knows that danger is likely inside cell (other similar looking cells were infected)

Induces apoptosis (via proteases and cytotoxins)

Functions of activated helper T cells (Th)

Also learned ‘danger’, seek out MHC II molecules (on self cells) with antigen matches

Cells that bind (B cells, macrophages) become activated

B cells eventually make antibodies via plasma cells

Macrophages gain ‘extra killing power’

Get bigger, get more lysosomes, produce toxic compounds

Natural Killer (NK) cells

Induce apoptosis in “self” cells

How do NK cells induce apoptosis in “self” cells

• recognize host cells that have foreign proteins in their proteins in their membrane covered in antibodies (Have receptors for Fc portion of antibodies)

• Deliver perforin and protease granules to cell… initiates

• Also recognize host cells lacking MHC I molecules (all self cells should be displaying inner contents - some viruses interfere with antigens presentation)

MHC I vs MHC II cells

MHC I = self

MHC II = non- self

What is adaptive immunity initiated by?

Dendritic ‘scout’ cells

(Gathers antigen for presentation to native T cells)

Tc activated and look for infected …

‘Self’ cells (harbouring antigen within the cell)

Induces apoptosis

Also produce cytokines to alert neighbours

Th cells look for …

Macrophages that have ‘eaten’ antigen of danger

Macrophage

Engulfs and destroys invaders, limited killing powers

What happens when Th cells activate macrophages that present antigen

Enhance macrophages killing powers

Adaptive immunity involves cells originating in the

Primary and secondary lymphoid organs

Th also activate … that have displayed the ‘danger’ antigen

B cells

If activated, B cells make …

Plasma cells

Memory cells of T and B cells help with adapting to the response …

Making it faster, more specific and efficient

Plasma cells make

Antibodies

(Tag extracellular antigen for removal)

Picture summary

How do so many different antibodies get generated

Gene rearrangement

What makes more combinations possible

Hypermutations

Gene junctions not being perfectly cut

Hypermutations

Happens after B cells activation… B cells have good match to antigen but could be better

Start mutating which improves antigen-antibody binding

Leads to additional super potent antibodies