Chapter 17A:Adaptive Immunity – Part I

1. Overview of Adaptive Immunity

2. T and B Cell Production

3. Antigens & Antigen Presentation

4. Helper T cells

1. Overview of Adaptive Immunity

The Nature of Adaptive ImmunityUnlike innate immunity, adaptive (acquired)immunity is highly specific and depends onexposure to foreign (non-self) material.

• depends on the actions of T and B lymphocytes (i.e., T cells & B cells) activated by exposure to specific antigens (Ag):

Antigen = any substance that is recognized by an antibodyor the antigen receptor of a T or B cell

**Only antigenic material that is “foreign” shouldtrigger an immune response, although “self antigens”

can trigger autoimmune responses.**

Recognize “processed” antigen via T cell receptor:

T cells

CD4+: helper T cells (TH) that activate other immune cells,regulatory T cells (TR) that suppress other T cells

CD8+: cytotoxic T cells (TC or CTLs) that kill infected orcancerous cells

free (soluble) or bound to B cell surface (B cell receptor)

B cellsProduce antibodies that bind to native antigens.

Humoral & Cell-Mediated ImmunityThere are 2 basic types of adaptive immune response (IR):

1) humoral IR• involves antibodies made by B cells & released into the

extracellular fluids (blood, lymph, saliva, etc…)

• deals with extracellular pathogens (or any extracellularforeign material)

2) cell-mediated IR• involves special cytotoxic T cells (CTLs) that kill cells

containing intracellular pathogens (e.g., viruses)

*both types of IR depend on helper T cells*

B cell

Humoral Immunity

antibodies

Cell-Mediated Immunity

Infected cell

T cell

antigen presented to T cell

antibody/antigencomplex

death of infected cell

Humoral vs Cell-Mediated Immunity

Connection to Innate ImmunityThe adaptive immune response is dependenton innate immunity in the following way:

• helper T cells (TH), which coordinate almost alladaptive immune responses, require processedantigen presented by certain phagocytes

• dendritic cells, macrophages & occasionally B cells

In this way, phagocytes involved in innate immune responses provide the adaptive part of the immune system with samples of what the body has been exposed to!

2. T and B Cell Production

Blood Cell Production

• stem cells are undifferentiated cells capable of giving rise to multiple cell types (and themselves!)

Hematopoietic stem cells in the bone marrowgive rise to all types of blood cells

• in reality, hematopoietic stem cells give rise to more specific stem cells:

Lymphoid stem cells – produce T & B cells (lymphocytes)

Myeloid stem cells – produce all other blood cells

Stem Cells & Blood Cell Production

From the Bone Marrow…Immature T cells 1st go to the thymus (via blood)

• in the thymus T cells undergo a maturation process referred to as “education”

• basically, this is where T cells that would react to“self antigens” are eliminated

• essential for preventing autoimmunity

B cells end up in lymph nodes, skin, gut or spleen• here they await foreign antigen they bind to• “self-reactive” B cells eliminated in bone marrow

• eventually end up in lymph nodes, skin, gut or spleen

Generation of Antigen Receptors Since there are millions of different T & B cellsand each produces a unique antigen receptor,how could this be encoded in the genome?

• the antibody (immunoglobulin) genes in each B cell,and the T cell receptor genes in each T cell undergoa somewhat random DNA recombination process

• in this way, the antigen receptor produced by eachT or B cell is unique (has nothing to do with foreign Ag)

• cells with a non-functional receptor die

• cells with a “self-reactive” receptor are eliminated

• cells that remain can only bind to foreign antigen!

Antigen Receptor Gene Recombination • the T cell receptor and immunoglobulin genes undergo

recombination to generate unique antigen binding regions

“variable region” “constant region”

Antigen ReceptorsEach T or B cell that survives development in the bone marrow or thymus has it’s own unique antigen receptor.

These “naïve” T and B cells do not become active unlessthey encounter antigen that binds their receptors…

ClonalSelection

Binding of antigenresults in:

1) mitotic division

**cells that don’t bind antigen within a few days die **

2) differentiation into

Effector cellsor

Memory cells

3. Antigens & Antigen Presentation

Native vs Processed Antigen (Ag)Native Antigen:

• antigen that is in its natural, functional state

• e.g., proteins that are folded “properly” (i.e., notdenatured or broken down)

• antibodies (soluble or as a B cell receptor)bind to native antigens

Processed Antigen:• antigen (usually protein) digested within a

phagocyte & presented in “pieces” on its surface

• the T cell receptor binds to processed antigen

Antibodies recognize Native Antigen

Epitopes on Native AntigensAn antigen can be a cell, a virus or a typeof macromolecule (usually a protein or polysaccharide).

The portion of an antigen that physically contacts a given antibody is called theepitope (aka “antigenic determinant”).

In other words, each antibody recognizes (i.e., binds to) a unique epitope on the native antigen it is specific for.

Processed AntigensProcessed antigens are of 2 types:

1) proteins produced within a cell (endogenous) are digested into peptides which are presented on the cell surface by MHC class I molecules

• occurs in almost all cells of the body• provides a “sample” of what is made in the cell to

CD8+ cytotoxic lymphocytes

2) peptides derived from material ingested by phagocytosis (exogenous) are presented on the cell surface by MHC class II molecules• occurs only in certain phagocytes to present samplesof exogenous antigen to CD4+ helper T cells

MHC-mediated Antigen Binding• CD8+ T cells (CTLs andregulatory T cells)recognize peptide antigens ONLY if presented on MHC class I molecules

• CD4+ T cells (helper T cells)recognize peptide antigens ONLY if presented on MHC class II molecules

**specificity of T cell activation depends on the peptide!**

• a T cell will only becomeactivated if its TCR “fits”the MHC/peptide complex

MHC Class I Antigen Presentation• endogenousproteins are“chopped up” intoshort peptideswhich fit into agroove in MHCclass I molecules

• these complexesare presented onthe cell surface toCD8+ T cells

• if the peptide is from a foreignprotein, the cell will be killed

(endogenousantigen)

Occurs in all cells!

MHC Class II Antigen Presentation

Phagocyte

Processed Exogenous AntigenCertain phagocytic white blood cells presentpeptides from ingested material within MHCclass II molecules on the cell surface:

• dendritic cells, macrophages, certain B cells• such cells are referred to as antigen presentingcells (APCs)

• MHC class II – peptide complexes arerecognized by CD4+ T cells (TH or TR)

• TH cells stimulated by foreign peptides in thisway initiate the 1st steps of the adaptive IR

**this is the key link between innate and adaptive immunity**

SuperantigensSuperantigens (such as those produced by certain bacterial pathogens) are rare molecules capable of stimulating T cells non-specifically by bridging MHC class II with the T cell receptor.

• regardless ofpeptide onMHC class II

• results in “wholesale”activation ofhelper T cells,intense IR(normal)

4. Helper T Cells

What do Helper T Cells do?As we’ve learned, adaptive immunityinvolves the following:

1) the production of antibody by B cells

2) the killing of infected cells by cytotoxic T cells

However, neither B cells nor cytotoxicT cells take action unless they receivecytokine signals from helper T cells :

• most are interleukins (e.g., IL-1, IL-2, etc…)

microbephagocyte

foreign antigen

1

MHC class II

23

4

5 6

7

APC interleukins

TH cellIL-2

IL-2 activatesother B and T cells

humoralimmunity

TC cell cellular immunity

B cellpresented antigen

TCR

TH cells become activated upon binding exogenous Ag• presented in MHC class II by an APC

TH cells then secrete cytokines activating B cells,TC cells & several other cell types

Activation of TH Cells

Two Types of Helper T CellsType 1 helper T cells (TH1):

• secrete cytokines to activate CTLs, NK cellsand macrophages

• trigger cellular immune response to deal withintracellular pathogens (e.g., viruses)

Type 2 helper T cells (TH2):• secrete cytokines to activate B cells, eosinophils

• trigger humoral immune response to deal withextracellular pathogens (e.g., most bacteria)

cytokinesTLR

antigenprocessing

The APC determines whether a naïve TH cell will become a TH1 or TH2 based on pathogen.

• via cytokines, cell-cell interactions

How does APC know the pathogen?APCs and other cell types express a variety of receptors that recognize Pathogen-Associated Molecular Patterns (PAMPs).

• Toll-like Receptors (TLRs) are an importantclass of PAMP receptor proteins

PAMP receptors such as TLRs reveal the type of pathogen present so that the appropriate innate and adaptive IRs are triggered.

• e.g., TLR3 binds dsRNA, TLR5 binds flagellin

Summary of Helper T Cell Function

1) APC (e.g., dendritic cell or macrophage) presents peptide antigens from what it “ate” on MHCclass II molecules & releases cytokinesreflecting the type of pathogen consumed

2) Any CD4+ TH cells with a T cell receptor thatrecognizes MHC class II presented peptides areactivated to become TH1 or TH2 cells

3) TH1 cells activate cells associated with cellularimmunity (e.g., CD8+ CTLs) , TH2 cells activate cells associated with humoral immunity (e.g., B cells)

Key Terms for Chapter 17A

• native vs processed antigen, epitope

• hematopoietic, lymphoid & myeloid stem cells

• humoral vs cellular immunity

• T cell receptor, B cell receptor

Relevant Chapter Questions rvw: 2-5, 10, 11, 14 MC: 5-7

• MHC class I & MHC class II

• interleukins, TH1 vs TH2 cells

• clonal selection• PAMPs, TLRs