W6.2 Flashcards
Chemokines
are a family of cytokines that enhance
motility and promote migration of many types of white blood cells toward the source of the chemokine (chemotaxis).
What chemokines direct in the body
- Most of the chemotactic activity of leukocytes is regulated by the activities of chemokines.
- Chemokines
- Chemoattractant Cytokines
- Induce concentration dependent chemotaxis of immune cells
- Also help activate cells
- Some constitutive some induced
- L-8, CCL2, fractalkine, SDF1
T cell activation and Immunologic Memory
- Remember, as lymphocytes differentiate and mature, they have different
functions and express different proteins (and “live” in different places) - Naïve T cells express CCR7-> lymph node homing CD62L -> entry into secondary lymphoid tissues via HEVs
- Effector T cells express receptors that cause them to migrate to different sites
(CCR5+α4β7 -> GALT, CCR5+CX3CR3->Lung CX3CR1+LFA-1-> vascular endothelium)
How cytokines and chemokines work togther
- Upon recognition of and activation by pathogens or PAMPs, resident macrophages in the tissue release cytokines such as IL-1, TNF-α and chemokines.
- IL-1 and TNFα cause the endothelial cells to express
cellular adhesion molecules (CAMs) and selectins - Chemokines recruit leukocytes to site of inflammation
Initiation of extravasation
1- selectin-mucin interactions mediate rolling
2- chemokines/chemoattractants induce change in integrins
3- Integrins adhere firmly to ICAMs
How cykotines work in the innate and adaptive immune response
Many cytokines can play a role in both the innate and adaptive immune responses. For example:
- IL-6 is a single protein produced by both lymphoid and nonlymphoid cells: T cells, B cells, monocytes and macrophages, fibroblasts, hepatocytes, keratinocytes, astrocytes, vascular endothelial cells, and various tumor cells.
- IL-1 primarily triggers secretion of IL-6.
IL-6 info
- IL-6 is a single protein produced by both lymphoid and nonlymphoid cells: T cells, B cells, monocytes and macrophages, fibroblasts, hepatocytes, keratinocytes, astrocytes, vascular endothelial cells, and various tumor cells.
- IL-1 primarily triggers secretion of IL-6.
- IL-6 is a pleiotropic cytokine, affecting inflammation, acute phase reactions, immunoglobulin synthesis, and the activation states of B cells and T cells.
- IL-6 stimulates B cells to proliferate and differentiate into plasma cells and induces CD4+ T cells to produce greater quantities of both pro- and anti-inflammatory cytokines.
cytokines of the adaptive immune response
mainly secreted by T cells, especially T helper (Th) cells, and affect T- and B-cell function more directly than was the case with cytokines in the innate immune response
Cytokine influence on Th cells
- There are three main subclasses of Th cells: TH1,
TH2, TH17, and Treg (Tregulatory cells). - Once the T-cell receptor (TCR) recognizes antigen, clonal expansion of those particular
CD4+ T helper cells occurs. - Differentiation into Th1, Th2, or Treg cell lineages is influenced by the spectrum of cytokines expressed in the initial response
Th1 cells
produce IL-2 (cell proliferation), interferon gamma (IFN-γ) and tumor necrosis factor-beta (TNF-β), which protect cells against intracellular pathogens
Th2 cells
- produce a variety of interleukins, including IL-4, IL-5, IL-10, and IL-13.
- The essential role of the Th2 cells is to help B cells produce antibody against extracellular pathogens.
Th1 cytokines
IFN-γ is the principal molecule produced by Th1 cells, and it affects the RNA expression levels of more than 200 genes
- These genes are involved in regulation and activation of CD4+ Th1 cells, CD8+ cytotoxic lymphocytes, NK cells, bactericidal activities, IL-12R, and IL-18R are all regulated by IFN-γ.
IFN-γ also stimulates antigen presentation by MHC I and MHC II molecules.
- Type II IFN (IFN-γ) is involved in regulation of cell function….typically NOT direct inhibition of viral
replication
IL-2 cytokine influence
- Th1 cytokines: IL-2: Th1 cells also secrete IL-2 in addition to IFN-γ. IL-2 is also known as the T-cell growth factor.
- IL-2 drives the growth and differentiation of both T and B cells and induces lytic activity in NK cells.
- IL-2 alone can activate proliferation of Th2 cells and helps to generate IgG1- and IgE-producing cells.
Th1 effector functions
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Th2 cytokines
- Th2 cells are primarily responsible for antibody-mediated immunity. (B cell activation and antibody class switching)
IL-4
- IL-4 is one of the key cytokines regulating Th2 immune activities and helps drive antibody responses in a variety of diseases.
- The IL-4 receptor is expressed on lymphocytes and on numerous nonhematopoietic cell types
Th2 effector functions
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Importance of Th1 vs Th2
- Leprosy (Mycobaterium leprae)
- Bacterium infects and lives inside macrophages
- Two main forms of disease
- Tuberculoid
- Primarily induces a cell mediated response (TH1)
- Forms granulomas and clear bacterium from macrophage
- *Lepromatous
- Primarily induces a humoral response (TH2)
- Bacteria cannot be controlled and lead to systemic disease
Treg function
- Tregs are CD4+ CD25+ T cells that are selected in the thymus.
- They play a key role in establishing peripheral tolerance to a wide variety of self-antigens, allergens, tumor antigens, transplant antigens, and infectious agents.
- Inhibit immune response by direct contact or by cytokines
- They produce IL-10 and TGF-beta
- Sidenote: IL-10 and TGFβ can be produced by several other cell types, including macrophages
Cytokines - Anti-inflammatory response
- The transforming growth factor beta (TGF-β) superfamily is composed of three isoforms: TGF-β1, β2, and β3.
- TGF-β was originally characterized as a factor that induced growth arrest in tumor cells.
- Later, it was identified as a factor that induces antiproliferative activity in a wide variety of cell types.
- Active TGF-β is primarily a regulator of cell growth, differentiation, apoptosis, migration, and the inflammatory response.
- Thus, it acts as a control to help down-regulate the inflammatory response when no longer needed.
TGF-beta function
- TGF-β inhibits the activation of macrophages and the growth of many different somatic cell types.
- It also functions as an anti-inflammatory factor for mature T cells.
- In activated B cells, TGF-β typically inhibits proliferation and may function as an autocrine regulator to limit the expansion of activated cells.
- TGF-β induces expression of Foxp3, a transcription factor that causes Treg cells to suppress the activity of other T cells.
IL-10 functions
- IL-10 has anti-inflammatory and suppressive effects on Th1 cells.
- It is produced by monocytes, macrophages, CD8+ T cells, Th2 and Regulatory (TREG) CD4+ T cells.
- It inhibits antigen presentation by macrophages and dendritic cells and stimulates CD8+ T cells.
- IL-10 serves as an antagonist to IFN-γ; thus it is a down-regulator of the immune response.
- T-cell suppression occurs through IL-10 inhibition of proinflammatory cytokines and inhibition of costimulatory molecule expression on antigen- presenting cells (APCs).
- TGF-β down-regulates the function of APCs and blocks proliferation and cytokine production by CD4+ T cells.
- These activities of IL-10 and TGF-β lead to down- regulation of the immune response and the prevention of chronic inflammation.
