Immunology #6: T-Cell Mediated Immune Response

List the major types of T-cells.

*Helper T-Cells (CD4/TH-Cells) 1. TH1 - inflammatory response 2. TH2 - anti-inflammatory response, B-cell activation, allergic reaction 3. TH17 - anti-inflammatory response 4. Treg - inhibit immune response *Cytotoxic T-Cells (CD8/TC-Cells)

Immune regulation is important because...

- Avoids excess lymphocyte activation and tissue damage - Prevents inappropriate reactions against "self" antigens - Helps balance activation and tolerance - Failure of immune regulation is the underlying cause of immune mediated inflammatory diseases

Describe peripheral regulatory T-cells.

- Develop from mature CD4 T-cells that are exposed to a persistent antigen in the periphery - NO role for thymus! - May be generated in all immune responses to limit damage - Can be induced in vitro by TGF-ß and IL-12

Describe thymic regulatory T-cells.

- Development requires recognition of self-antigen during T-cell maturation in thymus (thymic education) - Reside in peripheral tissues, prevent harmful autoimmune reactions

Describe cytotoxic T-cells (CD8/Tc Cells).

- Respond to antigens presented by MHC Class I molecules - Attack and kill infected target cells - Lyse targets by: 1. TNF-ß 2. Degranulation (granzymes, granulolysin, perforins) 3. Fas-induced apoptosis

Describe TH1 vs. TH2 differentiation.

- TH1 differentiation is driven by APC-derived cytokine IL-12 -TH2 differentiation is driven by cell-derived cytokine IL-4 *These cytokines are mutually antagonistic, leading to a strongly polarized response.

Describe the general features of helper T-cells.

- Utilize the amplification loop: produce cytokines to activate macrophages. - Differentiate into different T-cell subsets based on cytokine stimulation. - T-cell subsets must be stable (to provide adequate response) and plastic (to provide correct subsets). - Autoimmune and allergic reactions are associated with an imbalance of T-cell subsets

What are the main functions of TH17 cells?

1. Anti-fungal, Anti-bacterial 2. Organ-specific autoimmune disease (ex: psoriasis) 3. IL-17 induces expression of G-CSF and chemokines for inflammation with neutrophils 4. IL-22 induces antibacterial proteins 5. Causes chronic autoimmune inflammation in skin, joints, and CNS

Describe the phases of T-cell development.

1. Development in thymus 2. Naiive T-cells migrate out of the thymus into the blood 3. Priming phase: antigen-dependent differentiation in the lymphoid tissue (become memory and effector T-cells) 4. Effector phase: migration to sites of infection and effector function

What are the four phases of infection and immune response?

1. Establishment of infection 2. Induction of adaptive response via innate immune response 3. Adaptive immune response 4. Immunological memory

Describe the TWO categories of immune defense.

1. Innate Immunity: invariant (generalized), fast and early, limited specificity, "first line" of defense 2. Adaptive Immunity: variable (custom), later, highly specific, "remembers" infections, involves antigen-presenting cells (APCs) and lymphocytes

What are the main functions of TH2 cells?

1. Stimulate B-cells via IL-4 (cytokine) or CD-40 (cell-cell interaction) 2. Stimulate eosinophil activation via IL-5 3. Suppress macrophage activation via IL-10 and IL-4

What are the main functions of regulatory T-cells (Treg)?

1. Suppress immune cells such as T-cells, B-cells, dendritic cells, macrophages 2. Inhibition of immune response prevents autoimmune disease

What are the TWO major classes of regulatory T-cells?

1. Thymic (natural) regulatory T-cells 2. Peripheral (adaptive, inducible) regulatory T-cells

List the FIVE major classes of pathogens.

1. Viruses 2. Bacteria 3. Fungi 4. Protozoa 5. Worms

What is a granuloma?

A mass of aggregated infected macrophages surrounded by TH1 cells. - Serves as a major sign of chronic infection (ex: TB) - Pathogen persists in macrophages for a long time and insufficient macrophage activation by T-cells results in cell aggregation to limit the spread of pathogens.

Tc Cells

MHC: Class I MHC Activating Cytokine: IL-2, IL-12, INF-ɣ Cytokine produced: TNF-ß

TH1 Cells

MHC: Class II MHC Activating Cytokine: IL-12, INF-ɣ Transcription Factor: T-bet, Stat4 Cytokine produced: IL-2, INF-ɣ

TH2 Cells

MHC: Class II MHC Activating Cytokine: IL-4 Transcription Factor: GATA-3, Stat6 Cytokine produced: IL-4, IL-5, IL-10

Treg Cells

MHC: Class II MHC Activating Cytokine: TGF-ß, IL-2 Transcription Factor: FoxP3, Stat5 Cytokine produced: TGF-ß, IL-10, IL-35

TH17 Cells

MHC: Class II MHC Activating Cytokine: TGF-ß, IL-6, IL-23 Transcription Factor: RORɣt, Stat3 Cytokine produced: IL-17, IL-22

Describe the autoimmune consequences caused by the major T-cells.

TH1 Cells: + stimulated inflammation and auto-antibody production = autoimmune disease (ex: organ rejection) TH2 Cells: + stimulated IgE and eosinophil mediated inflammation = allergic reaction TH17 Cells: - stimulated acute inflammation = immune mediated disease (ex: psoriasis)

What are the main functions of TH1 cells?

TH1 cells regulate cell-mediated immunity by: 1. Control INTRACELLULAR pathogens, tumors 2. Mediate transplant rejection 3. Contribute to granuloma formation 4. Contribute to chronic inflammation 5. Activate macrophages!