Unit 3: The adaptive Immune Response

MMSC 415

Branches of the Adaptive Immune Response

Active, Passive, Adoptive

Active

can be either humoral immunity or cell-mediated immunity

What does an Active Adaptive Immunity means

Actively being exposed to something

What does a Passive Adaptive Immunity means

past to you

What does adoptive adaptive immunity means

getting someone else cells and you body adapting to them

Cell-Mediated Immunity

T-cell will tell what to do release B cells if needed

Type of Active Immunity

Naturally acquired and artificially acquired

Naturally acquired

Recovery from an infection

Artificially acquired

Vaccination

Passive

given preformed immune products

Naturally Acquired Passive Immunity

IgG crossing mother’s placenta, IgA in breast milk

Artificially acquired Passive Immunity

Intravenous Ig, mAb therapy

Role of Adoptive Immunity

Reconstitute the immune system, BMT, and CAR T-cell therapy

Hematopoiesis

is how blood cells are produced

What are Lymphocytes

B cells and T cells

Where Lymphocytes Develop

primary Lymphoid organs

What happens in the Lymphoid Organs

Development and maturation of lymphocytes, selection process (self vs non-self)

Where can you find B cells

the bone marrow

Where can u find T cells

T cell progenitor migrates to Thymus

Where Lymphocytes become activated

Secondary Lymphoid Organs

What happens in Secondary Lymphoid Organs

After maturation, lymphocytes enter circulation, may hangout in specific organs (encounter antigens, become activated)

Function of Lymph Nodes

Filter lymph fluid from draining tissue

B cells in Lymph Nodes

B cells concentrated in follicles and cortex

• Form germinal centers after B cells activated

T cells in Lymph Nodes

T cells concentrated in paracortex

Spleen

Filters blood, similar to lymph node

MALT (mucosa-associated lymphoid tissue)

non-encapsulated clusters of lymphoid tissue found int he mucous membranes lining the digestive, respiratory, urinary, and reproductive tracts

Largest immune and lymphatic organ system in the body

Gut-associated lymphoid tissue (GALT)

Role of M cells

to deliver antigens from gut to adaptive immune cells

Bronchial-associated lymphoid tissue (BALT)

a time of inducible or constitutive mucosal lymphoid tissue found along the airways. (Respiratory epithelium)

Major histocompatibility complex (MHC) or ( HLA)

Genetic capability to mount immune response linked to MHC

Function of MHC

found on all nucleated cells, brings small peptide antigen to cell surface, recognized by T cells

Where is MHC genes found

on short arm of chromosome 6

How is the MHC gene inherited

as haplotype, one chromosome from each parent, co-dominant

Class I of genetic control

all nucleated cells, six gene loci

Major Isotypes found in Class I

HLA-A, -B, -C

Minor Isotypes of Class I

MLA-E, -F, -G

Class II of genetic control

Antigen Presenting cells (APC), 5 Isotypes

The 5 isotypes of class II

HLA-DM, -DO, -DP, -DQ, -DR

Class III of Genetic Control

Not found on cells, Complement proteins

MHC/ HLA involvement

Transfusion reactions, transplant and graft rejections, autoimmune diseases

Transfusion reactions

Platelet, HLA-A

MHCI

Expressed on all nucleated cells

What does MHCI looks like

Glycoprotein dimer with two non-covalently linked polypeptide chains

MHCI chains

Alpha and Beta

Alpha chain

3 domains

Beta chain

encoded by single gene on chromosome 15, does not penetrate cell membrane, essential for alpha chain folding

MHCI function

endogenous antigens, intracellular pathogens

Intracellular pathogens in MHCI

Viruses, Tumor antigens, Degraded by proteasome, Peptides produced

Process of MHCI

Peptides transported to rough ER -→ Binds to MHCI (inside rough er) → Peptide-MHCI complex transported to golgi-→ Peptide-MHCI complex transported to cell surface → TCR binds antigen → MHCI binds co-receptor

MHCI binds co-receptor

CD8, CD8+T cell lyses cell

Classification of Immune Cells

• Cluster of differentiation

• Cell surface proteins

Cluster of Differentiation

CD Markers

Cell surface proteins

• USed to identify and classify immune cells

• Immature vs Mature

• B cell vs T cell

• More than 1 used typically

Role of MHCI

Bind viral/ tumor peptides, present to cytotoxic (CD8) T cell

Present to cytotoxic (CD8) T cell

10-100 identical antigen MHCI complexes needed to induce response, after contact CD8 T cell produces granzyme and perforin to lyse cell

MHCII

Expressed on antigen presenting cells (APCs)

APCs

monocyte, macrophage, dendritic cell, B cell, present exogenous antigens

Macrophages in MHCII

Kuppfer cells, Microglia, alveolar, etc.

Dendritic Cell

most effective

What is MHCII made up of

Two non-covalently bound poly peptides and alpha and beta chains

Alpha and Beta chains in MHCII

Both inserted into membrane, a1 and b1 regions from peptide binding

How does MHCII starts

Exogenous protein taken up

• Endocytosed

• Antigen processed into peptides in endosome

MHCII exits in rough ER

• Bound by invariant chain

• Binding blocked

MHCII leaves rough ER through Golgi

• Fuses with endosome

• Endosome cleaves invariant chain

• Peptide-MHCII complex can bind

How does MHCII ends

Peptide-MHCII complex transported to cell surface, TCR binds antigen, MHCII binds co-receptor

MHCII binds co-receptor

CD4

Role of MHCII

Clonal expansion of T cells (proliferation and activation)

T cells

The next step in adaptive immunity

How common are T cells in circulating Lymphocytes

75%

Markers of T cells

TCR, CD2, CD3, CD4, CD8

TCR

T cell receptor

CD2

sheep RBC receptor

CD3

part of TCR

CD4

co-receptor for MHCII

CD8

co-receptor for MHCI

TCR recognizes peptide-MHC complex

cannot bind antigen without MHC, every T cell has unique TCR

Two parts of TCR

• Antigen receptor

• CD3 glycoprotein

Antigen receptor TCR

• Alpha and beta chains

• Variable and constant region

• Similar to antibody

CD3 glycoprotein

Intracellular signaling

RAG proteins

give uniqueness to TCR

Recombination activating genes (RAG) 1 an 2

Responsible for rearrange gene segments of TCR, V(D)J recombination

RAG1/2 deficiencies prevent normal TCR formation

cause forms of SCID

Where does T cell maturation happen

in the thymus

Positive Selection

the first survival test

Positive selection test

Too strong (autoimmune), Intermediate (just right), Too weak (not functional)

What are T cells after Positive Selection

Single Positive

Negative Selection

removes self-reacting T cells

Self-antigen binding

autoimmune

No self-antigen binding

safe

How long is the T cell maturation process

takes around 3 weeks

What exits the thymus and enter circulation as SP and naive

CD4+ and CD8+

Subsets of T cells

• CD4+ Helper T cells

• CD8+ Cytotoxic T cells

CD4+ Helper T cells

Exogenous antigens presented by APCs using MHCII

Role of CD4+ Helper T cells

Coordinate immune response by releasing cytokines to activate and regulate other cells

CD8+ Cytotoxic T cells

Endogenous antigens presented by any nucleated cell using MHCI

Role of CD8+ Cytotoxic T cells

Kill virally infected cells and tumor cells, use perforin and granzyme

CD4+ Activation

Before binding MHCII-peptide complex T cell is called naive

Activation of CD4+ requires 2 signals

• TCR interaction with MHCII-peptide

• CO-simulatory molecules

TH1

Responsible for cell-mediated immunity through pro-inflammatory cytokines

Interferon-gamma (IFN-g)

• Stimulate macrophages

• Boosts tumoricidal activity

• Stimulates antigen presentation by MHCI and MHCII