Immmunology - Unit 3: The Adaptive Immune Response

what are the branches of the adaptive immune response?

adaptive → active, passive (passed on to you, ex. babies get IgG from mother), and adoptive (getting cells from someone else to produce immune product. ex. bone marrow transplant)

active→ humoral immunity (B-cells producing Abs) and cell-mediated immunity (T-cells use cytokines to tell cells what to do→ B-cells produce Ab after signaled by T-cells)

Active immunity

building your own defense

immune response produced by an immunocompetent individual following exposure to a challenge

Immune products produced → may take time (weeks) to develop; lifelong protection

Can be naturally acquired (ex. recovery from infection) or artificially acquired (vaccination)

what is an example of naturally acquired active immunity?

recovery from an infection

what is an example of artificially acquired active immunity?

vaccination

passive immunity

borrowing pre-made protection

given pre-formed immune products → transient protection acquired when preformed immune products are administered to an individual

confers immediate protection

Naturally acquired (ex. IgG crossing mother’s placenta, IgA in breast milk) or artificially acquired (Intravenous Ig, mAb therapy)

what is an example of artificially acquired passive immunity?

intravenous Ig, mAb therapy

what is an example of naturally acquired passive immunity?

IgG crossing mother’s placenta, IgA in breast milk

Adoptive immunity

transferring immune cells

transfer of immunocompetent cells from one individual to a second individual to establish immunocompetence in the second individual

Reconstitute the immune system→ ex. BMT, CAR T-cell therapy (cells recognize certain antigens and attack it)

what are examples of adoptive immunity?

BMT

CAR T-cell therapy

how are blood cells produced?

through hematopoiesis in the bone marrow

What are the lymphocytes (like B and T cells) formed from?

hematopoietic stem cell (bone marrow) → Lymphoid progenitor cell → T cell, B cell, or NK cell

B cell can further develop into plasma cell

where do lymphocytes develop?

primary lymphoid organs

• development and maturation of lymphocytes

• selection process→ self vs. non-self

Locations:

• Bone marrow → B cells

• Thymus → T cell progenitor migrates to thymus

where do B cells develop?

primary lymphoid organs → in the bone marrow

where do T-cells develop?

primary lymphoid organ→ progenitor migrates to the thymus

where are lymphocytes activated?

secondary lymphoid organs

• after maturation, lymphocytes enter circulation

• may hang out in specific organs → encounter Ags → activated

Ex. lymph nodes, spleen, mucosal-associated lymphoid tissue (MALT)

what are examples of secondary lymphoid organs

Lymph nodes, spleen, mucosal-associated lymphoid tissue (MALT)

Secondary lymphoid organs: lymph nodes

filter lymph fluid from draining tissue

B cells concentrated in follicles and cortex

• form germinal centers after B cells activated

T cells concentrated in paracortex

where are B cells in the lymph nodes?

follicles and cortex

• form germinal centers after ___ cells activated

Where are T-cells concentrated in the lymph nodes?

paracortex

secondary lymphoid organs: Spleen

filters blood

similar to lymph node

Secondary lymphoid organs: MALT

non-encapsulated

gut associated lymphoid tissue (GALT)

• Peyer’s patches, tonsils, adenoids

• M cells deliver Ags from gut to adaptive immune cells

Bronchial-associated lymphoid tissue (BALT)

• respiratory epithelium

what is GALT?

Peyer’s patches, tonsils, adenoids

M cells deliver Ags from gut to adaptive immune cells

what is BALT

respiratory epithelium

flowchart of how lymph nodes organize B- and T- cell encounters

Antigen found by APC → APCs enter draining lymph node → APC scan for cognate naive T-cell → T cell activated → clonal expansion and B cell interaction

what control is immune response under?

genetic control

linked to MHC → Major Histocompatability Complex/ HLA

• found on all nucleated cells → brings small peptide antigen to cell surface→ recognized by T-cells

where are MHC genes found?

short arm of chromosome 6

• closely linked

• inherited as a haplotype→ one chromosome from each parent, co-dominant

• >1.7 billion combinations gives diversity

what are the 3 classes of MHA/MLA

Class I → all nucleated cells; 6 gene loci (Major: HLA-A, -B, -C; Minor: MLA-E, -F, -G)

Class II→ Antigen Presenting Cells (APC); 5 Isotypes (HLA-DM, -DO, -DP, -DQ, -DR)

Class III → not found on cells; complement proteins

what are features of MHCI (expression and genes)

expressed on all nucleated cells

six gene loci:

• Major: HLA-A, -B, -C

• Minor: MLA-E, -F, -G

  • G: part of the placenta → produces inhibitory signals so that mother’s immune cells don’t attack baby

what are features of MHCII (expression and genes)

on Antigen Presenting Cells (APC)

5 Isotypes

• HLA-DM, -DO, -DP, -DQ, -DR

what are features of MHCIII (expression and genes)

not found on cells

complement proteins

Clinical relevance of MHC/HLA involvement

Transfusion reactions

• Platelet → HLA-A

Transplant and graft rejections

Autoimmune disease

Prevention → HLA matching

what is the structure of MHCI

glycoprotein dimer with 2 non-covalently linked polypeptide chains

• Alpha chain → 3 domains → a1 and 2 create a cleft for Ag; a3 binds CD8 and is inserted in membrane by cytoplasmic tail

• Beta chain

  • encoded by a single gene on chromosome 15

  • does not penetrate cell membrane

  • essential for alpha chain folding

what is the function of MHCI and the steps to that process

detect endogenous antigens

intracellular pathogens: viruses, tumor antigens → degraded by proteasome → peptides produced

peptides transported to rough ER → binds to MHCI

Peptide-MHCI complex transported to golgi → then cell surface

TCR binds antigen → MHCI binds co-receptor: CD8

CD8 + T cell lyses cell

How are immune cells classified?

CD markers

Cell surface proteins that can show immature vs. mature, B cell vs. T-cell

More than 1 used typically

what is the main role of MHCI

bind viral/tumor peptides

Present to cytotoxic (CD8) T-cell

• 10-100 identical Ag-MHCI complexes needed to induce response

• after contact, CD8 T-cell produces granzyme and perforin to lyse cell

what type of cells is MHCII expressed on?

Antigen presenting cells (APCs)

• Monocyte

• Macrophage

  • Kuppfer cells, microglia, alveolar, etc.

• Dendritic cell → most effective

• B cell

Present exogenous antigens

why are dendritic cells the most effective as APCs?

multiple arms that can bind/grab many Ags/ have a higher chance of grabbing Ags

what is the structure of MHCII

two non-covalently bound polypeptides

Alpha and beta chains

• both inserted into membrane by cytoplasmic tails

• a1 and b1 regions form peptide binding site → deeper than Class I, longer peptides

what is the function of MHCII and the steps to the process

present exogenous antigens

exogenous protein taken up → endocytosed

• Ag processed into peptides in endosome

MHCII exists in rough ER

• bound by invariant chain→ binding to other peptides now blocked

MHCII leaves rough ER thru Golgi

• fuses w/ endosome

• endosome cleaves invariant chain

• peptide-MHCII complex can bind

Peptide-MHCII complex transported to cell surface

TCR binds Ag and MHCII binds co-receptor (CD4)

Results in clonal expansion of T-cells → proliferation and activation

what is the main role of MHCII

Clonal expansion of T-cells

• Proliferation

• Activation → T cells able to do their job

what is the coreceptor/ T-cell type for MHCII when the T-cell binds

CD4

what is the coreceptor/ T-cell type for MHCI when the T-cell binds

CD8

what kind of immunity are T-cells a part of?

Cell-mediated immunity

main features of T-cells (size, amount, markers)

Small lymphocyte (7-10 µm)

75% of circulating lymphocytes

Markers:

• TCR: T cell receptor

• CD2: sheep RBC receptor

• CD3: part of TCR → normally how T cells classified

• CD4: co-receptor for MHCII

• CD8: co-receptor for MHCI

list the main markers found on T-cells

• TCR: T cell receptor → every T cell has unique one

• CD2: sheep RBC receptor → historically used to identify T-cells→ rosettes of sheep blood around cells

• CD3: part of TCR → normally how T cells classified

• CD4: co-receptor for MHCII

• CD8: co-receptor for MHCI

what gives T-cells their specificity?

TCR → recognizes peptide-MHC complex

• can’t bind Ag w/o MHC

• Every T cell has a unique TCR

  • Recognizes unique Ag

what are the two parts of the TCR?

Antigen receptor

• Alpha and beta chains

• variable and constant region

• similar to Ab

CD3 glycoprotein

• intracellular signaling → tell nucleus to turn on gene expression when T-cell activated

what proteins give uniqueness to TCR and how?

Recombination activating genes (RAG) 1 and 2

• rearrange gene segments of TCR → V(D)J recombination

RAG1/2 deficiencies prevent normal TCR formation → cause forms of SCID (Severe Combined Immunodeficiency)

what are the steps to T-cell maturation in the thymus in order?

T cell precursor migrates from bone marrow to thymus

Double negative T-cell (No expression of CD4 or CD8)

Double Positive T-cell (both CD4 and CD8 expressed on membrane)

Positive selection → binds to an Ag to make sure T-cell works (binding shouldn’t be too strong→ autoimmune or too weak→ non functional)

If T-cell survives, becomes singly positive (expresses either CD4 or CD8, but not both)

Negative selection → self-antigen presented to T-cell→ if it binds, apoptosis of T-cell

Mature CD4+ and CD8+ (SP) cells exit thymus → naive cells (have not encountered an Ag yet)

-takes ~3 wks, only 1% survive (positive/negative selection remove most)

What are the two subsets of T-cells

CD4+ Helper T cells

CD8+ Cytotoxic T cells

what are features of CD4+ Helper T cells?

exogenous Ags presented by APCs using MHCII

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

Called helper T cells (T_H) → B cell help, etc.

what are features of CD8+ Cytotoxic T-cells

endogenous Ags presented by any nucleated cell using MHCI

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

Called cytotoxic T lymphocytes (CTLs or T_C)

how are CD4+ helper T-cells activated?

Requires 2 signals:

• TCR interaction w/ MHCII-peptide

• Co-stimulatory molecules

T cells differentiate and effector T helper (T_H) cell or memory T (T_M) cell

• Effector T cell differentiation is based on environmental cytokines

T-helper cell 1 (Th1) - CD4+

typically pro-inflammatory

responsible for cell-mediated immunity thru pro-inflammatory cytokines

• Interferon-gamma (IFN-g)

  • stimulate macrophages

  • boosts tumoricidal activity

  • stimulates Ag presentation by MCHI and MHCII

• Interleukin-2 (IL-2)

  • Drives proliferation of both T and B cells

what does Interferon-gamma (IFN-g) produced by Th1 cells do?

• stimulate macrophages

• boosts tumoricidal activity

• stimulates Ag presentation by MCHI and MHCII

what does Interleukin-2 (IL-2) produced by Th1 cells do?

drives proliferation of both T and B cells

T-helper cell 2 (Th2) - CD4+

helps w/ antibody response

responsible for antibody-mediated immunity thru IL-4 production to help B cells turn into plasma cells

• Interleukin-4 (IL-4)

  • Interacts w/ IL-6 to drive B cells into plasma cells

  • Regulates other immune responses (ex. allergies, autoimmune responses, parasitic infections)

what does Interleukin-4 (IL-4) produced by Th2 do?

• Interacts w/ IL-6 to drive B cells into plasma cells

• Regulates other immune responses (ex. allergies, autoimmune responses, parasitic infections)

T regulatory (Treg) cells - CD4+

suppress inflammation

regulate immune cell activity thru anti-inflammatory cytokines

establish peripheral tolerance (in bloodstream→ tolerating own cells so they don’t attack self)

• Interleukin-10 (IL-10)

  • antagonist to IFN-g

  • inhibits Ag presentation by APCs

• Transforming Growth Factor-Beta (TGF-B)

  • regulates cell growth, differentiation, apoptosis, migration

what does Interleukin-10 (IL-10) produced by Treg cells do?

• antagonist to IFN-g

• inhibits Ag presentation by APCs

what does Transforming Growth Factor-Beta (TGF-B) produced by Treg cells do?

• regulates cell growth, differentiation, apoptosis, migration

what is key for proliferation of T-cells?

IL-2 → autocrine and endocrine function → T-cells release it during activation

anergy

T cells unresponsiveness after Ag recognition thru TCR

W/o co-stimulation (signal 2), T cells remain alive, but:

• reduced proliferation

• reduced cytokine production

how are CD8+ T cells (adaptive immunity) and NK cells (innate immunity) similar?

both are cytotoxic → use perforin and granzyme to kill

how are CD8+ T cells (adaptive immunity) and NK cells (innate immunity) different?

CD8 T cells are MCHI restricted thru TCR

NK cells don’t have TCR

• If cells have low or missing MHCI, that is a sign for NK cells to kill

• Use receptors as “do not kill” signal

• Also use ADCC (kill signal, Ab dependent cell-mediated cytolysis)

what are the characteristics of B cells (amount, type, markers)?

10-20% of circulating lymphocytes

APC

Part of HUMORAL IMMUNITY

Markers:

• Surface Ig: IgM and IgD

• IgG Fc receptor

• C3b receptor

• CD21 (EVB receptor)→ mono affects these cells b/c of this receptor

• MHCII

• Others: CD19, CD20, CD40 → markers to indicate it is specifically a ___ cell

what are the surface Ig’s on the surface of B cells?

IgM and IgD

List the markers on B-cells

• Surface Ig: IgM and IgD

• IgG Fc receptor → inhibitory signal to these cells to tell them Ab is no longer needed

• C3b receptor

• CD21 (EVB receptor)→ mono affects these cells b/c of this receptor

• MHCII

• Others: CD19, CD20, CD40 → markers to indicate it is specifically a ___ cell

what are the markers on B-cells that identify them as B-cells specifically

CD19, CD20, CD40

where does maturation of B cells occur?

bone marrow

List the steps/stages to the development of B cells

Develop in the bone marrow starting from a stem cell

stem cell → Pro-B cell

Pre-B cell - mu chains present in cytoplasm (will form into IgM)

Immature B cell - IgM expressed on the cell surface

Negative selection→ self-reactive B cells culled

IgM and IgD are expressed on surviving B cells

Naive B cells enter circulation

what protein makes every B cell specific to a unique Ag

BCR → the IgM and IgD on the cell surface

what proteins give uniqueness to BCR

RAG proteins → V(D)J recombination

what are the steps to B cell activation?

B cell binds to unique Ag thru BCR (IgM/IgD)

Leads to IgM capping

• all bound BCRs move to one “pole” on the cell → two Abs w/ 1 Ag bound btwn them → cross linking → activation

B cell now has two options:

• differentiate into plasma cell to produce Ab

• differentiate into memory cell to wait for later exposure

what happens when a B cell is activated by a thymus dependent (TD) antigen?

Ag is recognized by B cell → B cell processes it and presents it to a T cell

T cell is activated → releases cytokines to signal B-cell to activate/differentiate

B cell is activated and transforms into a plasma cell

• can produce all types of Igs (IgM, IgG, etc.)

what happens when a B cell is activated by a thymus independent (TI) antigen?

These antigens are polysaccharides that are recognized by B cell → long polysaccharide can cause cross-linking between Abs on B cell surface → activation

B cells only make IgM (will not class switch)

• ABO antigens

What happens during the primary antibody response to an Ag

first exposure to Ag

Latent phase:

• no detectable Ab

• ~14 days to activate cells and produce Abs

• First Ig appear: IgM

  • IgG follows (class switching in B-cells)

  • memory cells are formed

• Class switching → Changeover from IgM to IgG

  • same plasma cell producing IgM changes to produce IgG

  • Ag specificity remains the same

  • class switching is stimulated to T cell cytokines

Ig class switching - proliferation cytokines and differentiation cytokines

IL-2, IL-4, IL-5 → proliferation

IL-2, IL-4, IL-5, IFN-gamma, TGF-B → differentiation

what happens during secondary antibody response to an Ag

stronger than the 1st response

evokes anamnestic response

• rapid and intense

• shorter latent phase

• higher titer of Ig

• Predominant Ig: IgG

  • persists longer

affinity

strength of one Ag-binding site interacting w/ one epitope

depends on molecular fit and noncovalent interactions

avidity

overall functional strength of multivalent binding

depends on affinity, valency, geometry, and Ag arrangement

Comparison of primary vs. secondary response$

list the roles of Abs in infection

protection against infection

• opsonization

• complement fixation

• neutralization of pathogens

• cell lysis via ADCC w/ NK cells

role of Abs in diagnosis

IgM vs. IgG

• mother/baby → to measure baby’s immune response: IgM; for mother’s: IgG

Measure amt of antibody via titer

• Patient serum (Ab) reacts w/ Ag

• serial dilution → last dilution to react= titer