Immunology Exam from Study guides

Where does T cell maturation occur?

Thymus

What does the thymus provide?

The environment and stimulating signals for T cell proliferation and maturation

What do the majority of thymocytes differentiate into?

alpha,beta T cells

Order of T cell maturation in thymus

DN1, DN2, DN3, DN4, DN5, CD8 ISP, DP, CD4 SP/CD8 SP

When does proliferation happen T cells in thymus?

DN2, DN4, CD8 ISP

When does TCR Beta-chain rearrangement take place?

DN3

When does TCR alpha chain rearrangement occur?

DP

When does positive and negative selection occur?

DP

What is the order of types of cells in T cell maturation?

1.progenitor T cells, 2. Pre-T cells 3. Immature T cells 4.Mature T cells

Progenitor T cells

DN: CD3-, TCR-, CD4-, CD8-

Pre-T cells

DP: CD3+, TCRpTalpah:beta-, CD4+, CD8+

Immature T cells

DP: CD3+, TCRalpha-beta+, CD4+, CD8+

Mature T cells

Single positive: CD3+ TCRalphabeta+ CD4+, CD3+ TCRalphabeta+ CD8+

What are the 2 important events in T cell maturation?

TCR rearrangement, Thymus selection

TCR

T-cell receptor

What is selected for in positive thymus selection?

MHC restriction

What is selected for in negative thymus selection?

Self-tolerance

MHC

Major Histocompatibility complex

What T cells survive in positive thymus selection?

Recognize human MHC presented on CTEC with moderate affinity

cTEC

cortical thymic epithelial cells

What is the process of MHC 1 recognition?

DP cells TCR recognize and bind to MHC 1 then CD4 expression is shut down, creating CD4-CD8+ T cells

What is the process of MHC II recognition?

DP cells TCR recognize and bind to MHC II, CD8 expression is shut down, creating CD4+CD8- T cells

What cells are killed during negative thymus selection?

TCRs that bind too strongly to MHC

CD8 T cells

Cytotoxic effector cells, recognize MHC I

CD4 Th1 cells

Effectors activate macrophage, CTLs, and induce B cell opsonin production. Recognizes MHC II

CD4 Th2 cells

Activate B cells to produce multiple antibody classes, recognize MHC II

T cell mediated immune response steps

1.T cell recognize the antigen peptide-MHC complex, 2. T cell activation, proliferation, and differentiation

Double recognition (T cell mediated immune response)

T cells have dual specificity, so they recognize both self MHCs and peptide antigens displayed by MHC molecules

What produces signals that cause T cell activation?

Antigen-specific T cell receptor, adhesion molecules, and/or cytokines

How many signals are needed for complete T cell activation?

at least 2

Double recogntion

T cells have to recognize both the MHC and peptide presented for recognition

What do Adhesion molecules do?

Enhanced adhesion and immunological synapses

What is the CD8+ cell killing mechanism?

Conjugate formation, membrane attack, dissociation, targeted cell death

Which describes the rationale for a conjugate antibody?

Allows targeting of cancer cells for direct delivery of drug

Conjugate Formation

Cell adhesion and recognition of MHC I-antigen peptide on target cells

Membrane attack

Granules in cytotoxic CD8+ T cells cause exocytosis, Fas ligand to Fas triggers target cell death

Dissociation

Cytotoxic CD8+ cells interact for about 5 minutes, then dissociates to repeat conjugation

Target cell death

Target cell dies after a few hours after conjugation and membrane attack

Perforin action

Pore Forming on cell membrane, causing cell lysis

Granzymes

Act as nucleases, entering target cell and causing apoptosis

Fas-FasL pathway

Fas and FasL are induced upon T cell activation, mediated by Caspase. Causes DNA damage

T cell engineering approaches

Using tumor sample from patient, genetically engineering activating motif, or cloning human MHC genes

Tumor sample from patient T cell engineering process

Tumor sampled from patient, T cells are isolated from tumor, find tumor-specific TCR, engineer human T cell to express tumor specific TCR, expand population in culture, then give to patient

Genetically engineered T cell engineering approach

Genetically engineered activating motif is cloned to chimeric antigen receptor into retroviral vector, then human T-cell expressing chimeric antigen receptor specific for a tumor antigen, then given to patient

Clone human MHC T cell engineering

Clone human MHC genes, immunize mouse with human tumor antigens creating transgenic mouse for human MHC molecules, then isolate mouse T cell specific for MHC restricted tumor antigen, clone mouse TCR into retroviral vector, which creates human T cell expressing mouse TCR, then given to patient

TCR T vs CAR T cells

TCR is MHC dependent and has 1 antigen required on target, CAR T is MHC independent and has 100 antigens required on target

When is CD19 expressed?

All B cells and B cell precursors (except hematopoietic stem cells and Plasma cells). Also expressed by most B-cell malignancies

When is CD20 expressed?

B cells and most B cell precursors (not HSCs or Pro-B cells or plasma cells)

Common side effects of CAR-T cell therapy

Cytokine release syndrome, graft-vs-host disease, neurological symptoms, tumor lysis syndrome

Barriers for CAR-T therapy in solid tumor treatment

Immunosuppressive pathways, physical barriers, metabolic restriction, and immunosuppressive environment

Immunosuppressive cells in solid tumors

MDSC, Th17, Treg, TAM, DCreg, TAN

MDSC

Myeloid-derived suppressor cell

Th17

T helper 17 cells

TAM

Tumor-associated macrophage

DCreg

Regulatory dendritic cells

TAN

Tumor-associated neutrophil

Cytokines

Signaling proteins that regulate immune responses. Include interferons and interleukins

Interferons

Interfere with viral replication and activate the immune system

Interleukins

Act between leukocytes

IL-1

Produced by: TLR

Effects: Can breach blood brain barrier and causes fever

Interferon Y (IFNY)

Produced by: activated T lymphocytes and NKs and macrophages

Effects: Up regulation of HLA I and II expression

Tumor Necrosis Factor alpha (TNFalpha)

Produced by: Neutrophils and macrophages

Effects: Mediator of inflammation, prothrombotic activity and induces production of other cytokines

IL-2

Produced by: activated T cells

Effects: Autocrine activity, activation of lymphocytes and NKs. Used for solid organ transport

IL-4

Produced by: activated Th2 cells

Effects: promotes antibody production, T cell proliferation, used for allergies

IL-6

Produced by: B and T cells and Macrophages

Effects: Proinflammatory mediator (stimulates production of other cytokines and CRP), used to treat severe COVID

IL-8

Produced by: B macrophages, epithelial, airway smooth muscle, and endothelial cells

Effects: attracts neutrophils

IL-17

Produced by: Th-17 cells

Effect: autoimmunity, produced early in immune response and amplifies immune response. Implicated in several autoimmune diseases

IL-23

Produced by: activated macrophages and dendritic cells

Effects: Bridges innate and adaptive immunity, promotes expansion of Th17 cell, proinflammatory activity. Member of IL-12 family.

How does acute inflammation differ from chronic inflammation at the cellular level?

Acute inflammation is mediated by neutrophils and mast cells, with cytokines amplifying and ILs suppressing inflammation then tissue is repaired. Chronic inflammation is a persistent immune response of macrophages, lymphocytes, and fibroblasts and is not resolved quickly.

Why does chronic inflammation contribute to diseases like cancer and Alzheimer’s?

It promotes tumor initiation and progression with damage to DNA and altering tumor microenvironment. It also causes neurodegeneration.

What are the pathways of the arachidonic acid pathway?

Fatty acid released from cell membranes by either cyclooxygenase pathway (prostaglandins) or lipoxygenase pathway (leukotrienes)

Components of COX pathway?

Prostaglandin G2, H2, Prostacyclin, Thromboxane, Prostaglandin

Components of 5-LOX Pathway?

Leukotrienes

What response does prostaglandin make in Arachidonic acid pathway?

Pain and inflammation

What kind of response does Thromboxane make in arachidonic acid pathway?

Platelet aggregation

What do leukotrienes cause in arachidonic acid pathway?

Bronchoconstriction, asthma attacks, and smooth muscle contraction

Classes of antibodies

IgG, IgM, IgA, IgD, and IgE

IgG

Monomeric, most abundant, can pass through blood vessels, appears later in infection after B cell activation

IgM

pentameric (allows tight binding to multivalent antigens), Produced first in response to pathogens

IgA

Dimeric. Found in blood saliva and secretions

IgD

Less than 1%, monomeric, attached to surface of mature, naive B cells acting as receptor

IgE

Monomeric, low concentration in blood, binds to most cells to stimulate production of histamine and other mediators of allergy

Class switching

Activated B cells change class of antibody produced (switching immunoglobulin)

Antibody structure

4 chain structure with 2 identical light chains and 2 identical heavy chains

Affinity maturation

As antibodies continue to be produced, they have higher binding strength to a specific antigen over the course of immune response. Outcome is memory B cells or plasma cells with high affinity.

What is a plasma cell?

White blood cell that develops from activated B cells. Has high specific affinity

What is a memory B cell?

Long term, “remember” specific antigens to mount faster response upon re-exposure. Do not excrete antibodies on their own

Toxin neutralization

Opsonization

ADCC

Anitbody Dependent Cell cytotoxicity

How do antibodies work?

Each antibody has its own FcReceptor that binds to Fc to generate an immune response. They tag the invading cells for destruction or neutralization and activate the complement system.

Pinocytosis role in immune globulin function

Type of endocytosis that allows immune cells to sample, internalize and process antibodies and other soluble molecules. This allows for the antibody transfer through immune globulin therapy.

FcR role in immune globulin function

FcR binds to Fc of immunoglobulins, activating the immune cells.

Antigen presenting cells

APCs-cells that process and display antigens for T cells bound on MHC. Dendritic cells, macrophages, and B cells

Toll-like receptor

TLR-Recognize PAMPs, innate immune activation (complement and inflammation).

JAK inhibitor

Block JAK kinase, reducing inflammation and other immune signals (itching, redness, pain). Used primarily for autoimmune conditions such as arthritis.

JAK

Kinase that transmits cytokine signals, regulating inflammation and other immune responses

Major organs of the lymphatic system

Thymus, bone marrow

Where does B cell maturation occur?

Bone marrow (primary) and spleen (secondary)

Fetal liver (fetuses in early pregnancy)

Where do B cells encounter antigens?

Blood and lymphatic system or lymph nodes and spleen