Lecture 146: Immunogenetics, Lymphocyte Activation, Immune Regulation Tolerance II

Immunological synapse

region of contact between APC and T cell including redistributed proteins

• causes early events such as tyrosine phosphorylation of molecules of TCR complex + recruitment of adapter proteins to site of T cell antigen recognition - TF activation

Clonal expansion

within 1 or 2 days after activation - T lymphocytes proliferate - expansion of antigen specific clones

• this helps the adaptive immune response to keep up with rapidly dividing microbes

Differentiation of Naive T cells to Effector Cells

CD4 cells differentiate into effector cells - respond to antigens on surface molecules - activate phagocytes + B lymphocytes - produce Th1 and Th 2 cells

Differentiation of CD4 native cell types

Development of Memory T lymphocytes

some T cells differentiate to memory cells that survive after infection is gone

• Location: lymphoid organs, mucosal tissues

Central memory cells: in lymphoid organs: responsible for rapid clonal expansion after exposure to antigen

Immunological ignorance

antigen specific unresponsiveness: being able to recognize self antigens but not respond to it

• if this fails: autoimmunity

Central tolerance

T cells: cell death
CD4 cells: generation of T reg cells

Negative selection: destroy lymphocyte that binds too strongly to MHC or binds to self antigen (triggers apoptosis)

• doesn't complete maturation

Main processes in Central tolerance

Peripheral tolerance

Peripheral tolerance is induced
= when mature T cells recognize self antigens in peripheral tissues, leading to functional inactivation (anergy) or death,

or when the self-reactive lymphocytes are suppressed by regulatory T cells

Positive selection

• takes place in cortex of thymus
• cortical epithelial cells, which express MHC class I & II molecules bind T cells, which have receptors for our own MHC molecules
• -cell receptor that binds to a self-MHC class I molecule on thymic cortical epithelial cells in the thymus, are signaled to survive
• no binding to MHC I: die

Negative selection

deletion of strongly self- reactive T cells in the thymus.
• T cells that have undergone positive selection then go
to the thymic medulla where they undergo negative
selection

Combinations of positive and negative selection

How are anergy and CTLA4 forms of tolerance?

Anergy: inactivation of T cells when not enough co stimulation is present for full T cell activation

CTLA4: can bind to B7 shutting off T cell response

• interferes with binding of CD28/B7

Immune suppression by Regulatory T cells

develop in the thymus or peripheral tissues upon recognition of self antigens

• they block the activation of potentially harmful lymphocytes specific for these self antigens.
  • Most regulatory T cells are CD4+ and express high levels of CD25

Function of FOXP3

• binds to specific regions of DNA
  important in activating Treg - inhibits T cell activation and effector functions

Activation Induced Cell Death

Self antigen recognition - apoptosis

• Death receptors + Fas and Fas ligand leads to apoptosis

What influences between t cell tolerance and activation?

Central B vs Peripheral B cell tolerance

Central: Receptor editing (expression of new receptor) or apoptosis (negative selection)

Peripheral:

• A mature B cell that recognizes a self antigen without T cell help is functionally inactivated and becomes incapable of responding to that antigen.
  Mature B cells that are partially activated by recognition of self antigens without T cell help may die by apoptosis

Immune responses against Transplants

What is the principal targets of rejection?

Antigens of allografts which are proteins encoded in MHC complex

• recognition of MHC antigens on another individual's cells is one of the strongest immune responses

Indirect vs direct recognition

Indirect:

• T cell recognizes processed peptide of allogenic MHC molecule bound to self MHC molecule on host APC

Direct:

• T cell recognizes unprocessed allogenic MHC molecule on graft APC

Acute transplant rejection

several days or weeks after transplantion

• principal cause of graft failure
• mediated by CD8 cells against allo antigens in graft

Cause of acute transplant rejection

direct pathways of allorecognition that involves activation of recipient T cells by dendritic cells from donor

Hyperacute rejection

occurs within minutes

• thrombosis of graft vessels and ischemic necrosis of graft
• mediated by circulating antibodies, specific for antigens on graft cells - present in recipient before transplantation
• antibodies are specific for blood group antigens or abs specific for allogenic MHC molecules

How do you minimize hyperacute rejection?

cross match testing

• Test donor WBCs against recipient serum

• If recipient has pre-formed antibodies → cell lysis

• Negative crossmatch = safe to proceed

Chronic Rejection

months to years

• progressive loss of graft function
• To prevent: give immunosuppressant drugs
• fibrosis of graft tissue and bv

Graft vs host transplant rejection

common with bone marrow transplant and liver transplant

• grafted immunocompetent T cell proliferate in host and reject cells with foreign proteins

• jaundice, hepatosplenomegaly, diarrhea, maculopapular rash

Tumor cell killing by T cells

A 50 year old male with chronic renal failurehad a cadaveric renal transplant that was successful asdetermined by the production of urine during thesurgery. Two weeks later, his creatinine level began torise and urine production decreased. UA was normal. Abiopsy was taken from the kidney which revealed aninfiltrate.

Which of the following would most likely be found on the surface of the cells responsible for his condition?

a) CD 20
b) CD 27
c) CD 4
d) CD 8
e) CD 9

D

A) Antigen presentation and destruction of intracellular pathogens

B) Defense against parasites and other pathogens by eosinophils

C) Immediate allergic hypersensitivity reaction involving IgE

D) Neutrophil chemotaxis

E) Antibody secretion by plasma cells

A

A 48-year-old female with late stage chronic renal failure from diabetes undergoes renal transplantation. Urine production is adequate post- operatively. 8 months later for a follow-up visit, she has a BUN/Cre level well above normal and complains of decreased urine production with symptoms of headache and back pain. A biopsy reveals what is shown on the next slide. What is the pathogenesis of this condition?

A. Damage due to infiltrating neutrophils & basophils

B. Damage due to infiltrating dendritic cells

C. Damage due to infiltrating T cells & macrophages

D. Damage due to binding of IgA + complement

C

Due to time passed since transplant

The role of CD3 proteins and the zeta chain on the surface of the cell is to:

a) transduce signals to the interior of the T cell

b) bind to antigen associated with MHC molecules

c) bind to MHC molecules on the APC

d) bind to CD4 or CD8 molecules

e) facilitate antigen processing of antigens that bind to the surface of T cells

A

Which of the following accurately completes this statement: “The function of ____ T cells is to make contact with ____ and ____”? (Select all that apply.)

a) CD8; virus-infected cells; kill virus-infected cells

b) CD8; B cells; stimulate B cells to differentiate into plasma cells

c) CD4; macrophages; enhance microbicidal powers of macrophages

d) CD4; B cells; stimulate B cells to differentiate into plasma cells

e) All of the above

A, C, D

Several years ago, the famous musician Bob Dylan developed a somewhat unusual fungal infection affecting his heart. This type of infection is typically associated with a certain defect of the immune system and is endemic in certain parts of the Midwest. What is the name of the fungal infection that caused his endocarditis, and the nature of the immune defect ?

A. Cryptococcosis; loss of Th2 function

B. Candidiasis; defect in neutrophil activation

C. Nocardiosis; apoptosis of activated macrophages

D. Histoplasmosis; impairment of Th1 function

E. Coccidiomycosis; failure of antigen processing by dendritic cells

D

B/c of location

Which of the following explains why dendritic cells are more efficient than macrophages at stimulating naive T cells?

a) Macrophages do not express MHC class II molecules

b) Dendritic cells are migratory and transport antigen to neighboring secondary lymphoid tissue.

c) Dendritic cells do not repair damaged tissues.

d) Macrophages process only polysaccharide antigens.

e) Dendritic cells, but not macrophages, endocytose foreign antigen

B

An adjuvant enhances the effectiveness of vaccines by inducing the expression of ____ on ____.

a) Co-stimulatory molecules; dendritic cells

b) CD28; macrophages

c) MHC class II molecules; T cells

d) T-cell receptor; T cells

e) Immuno-receptor tyrosine-based activation motifs; dendritic cells

A

Immune checkpoint blocking therapies (ICBTs) have been implemented in the clinic to treat a variety of malignancies based upon their ability to:

A. Activate memory T cells to stimulate B cells

B. Enhance antibody production & binding to C’

C. Target T-cell inhibitory molecules or receptors

D. Prevent apoptosis of cytotoxic CD8 T cells

E. Increase phagocytosis by neutrophils

C

Immunologic Synapse Formation Key Molecules

- Involves TCR, CD3, CD4/CD8

- Co-stimulatory molecules (CD28 on T cell ↔ B7 on APC)

- “SMAC” = Supramolecular Activation Complex

 Antigen Recognition Key Molecules

- CD4 binds MHC II

- CD8 binds MHC I

- Trigger early signaling

Signal Transduction Key Molecules

- Tyrosine phosphorylation of CD3 ζ-chain

- Adaptor proteins like ZAP-70

- Activates transcription factors: NF-κB, NFAT, AP-1

Clonal Expansion Key Molecules

- Driven by IL-2 secretion and IL-2 receptor (CD25) expression

Differentiation Key Molecules

- CD4+ → Th1, Th2, Th17, Treg

- CD8+ → Cytotoxic T cells

Mnemonic: "Signal 1 = TCR; Signal 2 = CD28-B7; Signal 3 = Cytokines"

• No Signal 2 → Anergy

• IL-2 = "T-cell growth factor" (autocrine)

Allorecognition

Cause of acute rejection of transplanted tissues or organs, involves activation of recipient’s T cells by dendritic cells of donor origin

Th1 Inducing Cytokines

IL-12, IFN-γ

Th2 Inducing Cytokines

IL-4

Th17 Inducing Cytokines

TGF-β + IL-6

Treg Inducing Cytokines

TGF-β + IL-2

Th1 secretes

IFN-γ

Th2 secretes

IL-4, IL-5, IL-13

Th17 secretes

IL-17, IL-22

Treg secretes

IL-10, TGF-β

Th1 fx

Activates macrophages & CD8+ T cells; intracellular pathogens

Th2 fx

Stimulates eosinophils, IgE; fights helminths

Th17 fx

Recruit neutrophils; extracellular bacteria, fungi

Treg fx

Suppresses immune responses

Tolerogenic Self Antigens - Presence in Generative Organs

Yes (some self antigens); high concentrations induce negative selection or Tregs → central tolerance

Immunogenic Foreign Antigens - Presence in Generative Organs

No; microbial antigens are instead found in peripheral lymphoid organs

Tolerogenic Self Antigens - Presentation with Second Signals (Costimulation, Innate Immunity)

No; absence of costimulatory signals can lead to T cell anergy or apoptosis

Immunogenic Foreign Antigens - Presentation with Second Signals (Costimulation, Innate Immunity)

Yes; microbes typically trigger costimulatory molecules → T cell survival and activation

Tolerogenic Self Antigens - Persistence of Ag

"Long-lived (throughout life); prolonged TCR engagement may result in tolerance via anergy or apoptosis

Immunogenic Foreign Antigens - Persistence of Ag

"Usually short-lived due to immune clearance

Syngeneic

Grafts between genetically identical individuals (e.g., identical twins)

Allogeneic

Same species, genetically different

Xenogeneic

Between different species (e.g., pig valve to human)

Allograft

Graft between genetically different humans (most common)

Checkpoint Inhibition - Mechanism for Tumor Immune Evasion

Tumors express PD-L1 or CTLA-4 ligands to turn off T cell response

Low MHC I Expression - Mechanism for Tumor Immune Evasion

Escape CD8+ detection

Immunosuppressive Cytokines - Mechanism for Tumor Immune Evasion

IL-10, TGF-β from tumor or stroma suppress immunity

Anti-CTLA-4 - Immune Checkpoint Inhibitor

Blocks inhibition of T cells at early stage and promotes activation

Anti-PD-1 / Anti-PD-L1 - Immune Checkpoint Inhibitor

Blocks peripheral T cell inhibition and restores cytotoxic activity