L8: Immunoregulation

Question 1

Treg cells. What cytokine(s) do these cells need in order to develop? What cell surface markers do they express that are necessary for their function?

Answer 1

• Require TGF-beta for development as it induces expression of FoxP3, which is a transcription factor. Also requires IL-2, an essential GF.
• Expresses CD4+ and CD25, which is the alpha chain of the IL-2 receptor. Expresses high levels of CTLA-4, which inhibits the activation of T cells

Question 2

Function of Treg cells?

Answer 2

• Prevents excessive immune responses to foreign antigens

- Prevents immune responses to self antigens missed by tolerization

Question 3

What are Treg cells mechanisms of action to down-regulate the immune system? What cytokines does it produce, and what are their functions?

Answer 3

• Produces suppressive cytokines IL-10 and TGF-beta (same thing required for its development)
• IL-10 inhibits IL-12 production by DCs / macrophages and downregulates expression of costimulatory molecules and class II MHC by these cells
• TGF-beta suppresses activation of macrophages and T cells and promotes development of Treg cells
• Treg cells use their CTLA-4 to bind B7 molecules on APCs, thereby reducing ability of APCs to activate T cells
• Lastly, they consume IL-2, thus depriving other cells this GF

Question 4

How does antibody feedback play a role in downregulating the immune system?

Answer 4

• Antibody helps eliminate the antigen, therefore no further stimulation by antigens
• Immune complex-bound antibodies inhibit B lymphocyte activation (Note: antibody must be bound to antigen (ie. be in complex form) and complex binds to FC receptors on B-lymphocyte)

Question 5

What is immunological tolerance? Why is this beneficial?

Answer 5

• Induced state of unresponsiveness to antigens

- Beneficial: loss of tolerance to self prevents autoimmune disease

Question 6

Two types of tolerance. What specifically is happening in each?

Answer 6

1. ) Central tolerance (in thymus, bone marrow): apoptosis, receptor editing and development of Treg cells
2. ) Peripheral tolerance: anergy, apoptosis, suppression

Question 7

What is clonal deletion? Clonal anergy?

Answer 7

• Clonal deletion: death of antigen-specific lymphocytes

- Clonal anergy: inactivation of viable lymphocytes causing them to be unresponsive to antigen, but not via death

Question 8

Describe mechanisms of T cell tolerance in the periphery

Answer 8

1. ) Via Treg cells
2. ) T cells-APC interaction without costimulatory molecules. Remember, that MHC class I and II place self antigens on their surfaces as place holders until such time that pathogens are present. If costimulatory molecules were present, T cells would react against self

Question 9

Describe mechanisms of B cell tolerance

Answer 9

1. ) Immature B cells exposed to antigen in bone marrow = clonal deletion OR
2. ) Receptor editing: B cell rearranges light chain genes to produce completely different antigen specificity. If it doesn’t recognize self, then cell survives. If it does, clonal deletion

Question 10

What happens to thymocytes under corticosteroid therapy?

Answer 10

• Destruction of thymocytes. Chronic therapy leads to immunodeficient state

Question 11

Selection processes of thymocytes in thymus. What cells mediate these processes?

Answer 11

1. ) Positive selection: thymocytes that bind self MHC are permitted to survive, elimination of thymocytes that recognize foreign MHC proteins. Cortical epithelial cells mediate positive selection
2. ) Negative selection: thymocytes that bind self antigens and self MHC eliminated. Carried out by DCs at corticomedullary junction

Question 12

Failure of which thymocyte developmental process is more dangerous: positive or negative selection?

Answer 12

• Negative selection failure is more detrimental. If these cells survive, they bind self MHC carrying self antigens and autoimmune disease results. Failure of positive selection is not deleterious as the cells that survive will recognize foreign MHC with self or foreign antigen.

Question 13

What is the AIRE gene?

Answer 13

• Autoimmune regulator gene
• Thymus can express tissue specific self antigens that aid in the negative selection process in the thymus (conducted by DCs). Expression of tissue-specific proteins are under the regulation of the AIRE gene.

Question 14

What is IPEX syndrome?

Answer 14

• Autoimmune disease: immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome
• Result of absence of Treg cells

Question 15

Categories of cytokines. What cells produce them and what do they regulate?

Answer 15

1. ) Monokines: produced by macrophages
   - regulates phagocytic cells
2. ) Lymphokines: produced by activated T cells
   - regulates lymphocytes, macrophages, neutrophils, eosinophils
3. ) Colony-stimulating factors: produced by lymphocytes, macrophages, bone marrow stromal cells
   - regulates granulocytes and monocyte production in bone marrow

Question 16

TNF-alpha. What cells produce this? In response to what? Biological actions?

Answer 16

1. ) Produced by mononuclear phagocytes and T-lymphocytes
2. ) In response to bacterial LPS (aka endotoxin)
3. ) Actions: activates macrophages/neutrophils, DIC/shock, neutrophilia, fever generation, increased adhesiveness of vascular endothelium for neutrophils

Question 17

Describe pathologic systemic effects of TNF?

Answer 17

• Decreases contractility of heart leading to low output
• Thrombus formation, increased permeability of endothelial cells (hypotension)
• Insulin resistance in multiple tissues leading to decreased ability to uptake glucose

Question 18

IL-2. Produced by what cells. Function?

Answer 18

• Produced by CD4+ T-cells
• Acts as autocrine and paracrine growth factor for T cells. Also increases NK cell cytotoxicity and at high concentrations induces NK cells to become lymphokine-activated killer cells (LAK cells)

Question 19

IL-4. Produced by what cells. Function?

Answer 19

• Produced by CD4+ T cells, mast cells and basophils

- Induces B cells to isotype switch to IgE. Also induces TH2 immune response

Question 20

TGF-beta. Produced by what cells. Function?

Answer 20

• Produced by activated T cells and activated macrophages
• Induces TH17 cells, inhibits T cell proliferation/differentiation into CTLs, inhibits macrophage activation, induces B cells to produce IgA at mucosal sites, initiates wound healing (fibroblast migration/proliferation and collagen synthesis)

Question 21

IFN-gamma (aka type 2 interferon). Produced by what cells. Function?

Answer 21

• Produced by CD4+ and CD8+ T cells. Also by NK cells
• Most potent activator of macrophages. Directs immune response toward cell-mediated immunity, upregulates class I and II MHC expression, induces isotype switching to IgG