T cell differentiation/effector functions Flashcards
CD4 T cell can become what types of CD4 cells
- TH2
- Treg
- TH17
- TH1
- Tfh (T follicular heper cells)
Cytokines made by TH2
IL4, IL13, IL5
Cytokines produced by Treg
IL10
TGF-beta
Cytokines produced by TH17
IL17
Cytokines produced by TH1
IFNy
TH2 cells become
Eosinophils
Basophils
Mast cells
Macrophages
Barrier immunity
Treg cells become
Dendritic cells
Inhibition of other effector T cell types
Th17 cells become
Neutrophils
acute inflammation
TH1 cells become
Activated macrophages, NK cells and CD8 T Cells
Systemic immunity
Three signal hypothesis
- MHC peptide
- Costumulation (B7-1, B7-2)
- Cytokines (IL12)
Signals 1 and 2 induce:
Signals 3 instructs:
T cell activation
T cell differentiation
Cytokines and T cell differentiation
usually only one or two of these would be the dominant cytokine produced
(IL6, IL12, TGFbeta, IL4)
Th1 functions
- Protects against intracellular pathogens and tumors
- Support CD8 T cell response (via IL2)
- Activate phagocytes ( macrophages) that will kill the pathogen via respiratory burst and dispose of cells that were killed as a result of infection
- Recruit NK cells to kill infected cells (often virus infection induces downregulation of MHC class I)
- Signature cytokine product: IFN-gamma
- Major cytokine that it induces: IL-12
IFN-gamma works against
- inhibits TH2 responses
- induces macrophage activation. Increases MHC class I and II
Individuals lacking IFN-gamma
susceptible to mycobacteria, and some viruses
IFN-gamma functions
Macrophages
- activation, increased microbicidial activity
B- cells
- Isotype switching to opsonizing antibodies
Naive CD4+ T cells
- Development of TH1 effector cells
Antigen presenting cells (APC)
- Increased MHC expression, antigen presentation
IL12 induces
IFN-gamma
CD4+ Effector T cell (TH1 cell) + Macrophage
TH1 secretes IFNgamma into macrophage while it is bound to macrophage through CD40L-CD40 interaction
Response:
- increased production of ROI and NO in macrophage
- Increased killing of phagocytosed microbed
- Increased expression of costimulators (B7 molecules)
- Secretion of Cytokines (TNF, IL1, IL12)
- Increased expression of MHC molecules
Which of the following would at Th1 response be the best?
Intracellular bacteria = Th1
Th2 Functions
- Provide protection against multicellular parasites and mediate hypersensitivity responses
- Provide proliferative signals to B cells
- Drive B cell isotype switching to IgG1 and IgE
- Often associated with allergy (due to IgE production and recruitment of mast cells)
- Signature cytokine product: IL-4
- Major cytokine that it induces: IL-4
IL4 (TH2)
- ## Works against TH1
Th1 and Th2 responses are
antagonistic to eachother
Th2 produces
- IL4/IL13
- IL5
- IL3/IL9
IL4/IL13 (Th2)
Alternative activaiton of macrophages IgE production from B cells, activation of epithelial cells and smooth muscle cells
- Macrophage
- B cell
- Epithelium
- Smooth Muscle cell
IL5(Th2)
Recruitment and survival of eosinophils, IgA production from B cells
- Eosinophil
- B cell
IL3/IL9 (Th2)
Recruitment and survival of mast cells and basophils
- basophil
- mast cell
Actions of IL4
B cell
- Isotype switching to Ige and IgG1
Macrophages
- inhibition of macrophage activation
Naive CD4+ T cell
- development and expansion of Th2 cells
Leprosy, caused by
intracellular bacteria, Mycobacterium leprae
Leprosy definition
a paradigm of T cell helper differentation
The type of T helper response elicited determines the outcome of infection: two main presentatins of the disease:
Tuberculoid
- Th1 type CD4+ T cell response
- IFNgamma activates macrophages
- Macrophages then destroy intracellular bacteria
The type of T helper response elicited determines the outcome of infection: two main presentatins of the disease:
Lepromatous
- Th2 type CD4+ T cell response
- IL4 inhibits macrophage activation
- Macrophage unable to kill intracellular bacteria
Tuberculoid Leprosy
- Organisms present at low to undetectable levels
- Low infectivity
- Granulomas (structure containing infected cells) and local inflammation + peripheral nerve damage
- Normal serum immunoglobin levels
- Normal T cell responsiveness. Specific response to M. Leprae antigens
Mild, under control
Lepromatous Leprosy
- Organisms show florid growth in macrophages
- high infectivity
- Disseminated infection. Bone, cartilage, and diffuse nerve damage
- Hypergammaglobinemia
- Low or absent T cell responsiveness. No response to M. Leprae antigens.
Severe, poorly controlled
APC + Naive CD4+Tcell = Activated T cell
Activated T cell
- IL12
- Activated macrophages, dendritic cells
- Leads to Th1 cells - IL 4
- From other cellular sources
- Leads to Th2 cell
Th17 Cells
- Recently discovered CD4 subset that is proinflammatory
- Mainly protects against extracellular bacteria by recuirting neutrophils
- Often associated with autoimmine disorders
- major cytokine product (IL17)
- Major cytokines that induce: TGFbeta and IL6
Acts on other cells that produce IL6 and chemokines that recruit Neutrophils.
Th17 appear early in infection
before Th1 and Th2
TGFbeta by itself leads to..
‘
TGFbeta + IL6 leads to..
Treg cell
Th17 cell
Th17 cell differentation
To become a Th17 cell a naive CD4Tcell must be exposed to TGFbeta and IL6. If the naive cell is exposed to TGFbeta alone, it will become a Treg cell
Th17 produced cytokines
IL17 - activated endothelial cells (which then recruits neutrophils via IL6)
Treg cells ( T regulatory cells)
- Tregs, acts to suppress immune responses
- T cells express CD4 and CD25 (alpha chain of IL2), were found to be highly enriched in suppressor activity (could prevent autoimmune disease)
- FOX23 is the transcription factor that regulates the Treg phenotype.
T regualtory signature cytokines
- IL10 - Reduces production of IL12 and TNFalpha, reduces expression of MHC and costimulatory molecules
- TGFbeta - blocks cytokine production, proliferation of T and B cells, and cytolytic activity
Both are very suppressive cytokines
- shut down immune responses
Treg cells are very efficient at shutting down
autoimmine T cell responses
Tumors and Tregs
T regulatory cells can have a negaitve effect.
Tumors secrete TGFbeta which induces Tregs at the tumor site to suppress anti-tumor respones.
FOXP3 drives
functional properites of Tregulatory cells
T follicular helper cell (Tfh)
- reside within lymphoid follicles ( B cell zone)
- Provide help to B cells for class swtictching., and high affinity antibody production
- Distinct lineage from Th1 or Th2, but can produce cytokines typical of either one
Signature cytokine: IL21
TGFbeta signal on a T cell, leads to production of
Treg cells, which then produce TGFbeta and IL10
IL6 signal on a T cell leads to production of
Tfh cell, which then produce IL21
Main function of Tfh
Isoptype switching and affinity maturation in B cells
TGFbeta and IL6 signal on a T cell leads to prudction of
Th17 cells, which then produces Th17
IL12 signal on T cells produce
Th1 cells, which then produce IFNgamma
IL4 signal on a T cell produce
Th2 cells, which then produce IL4
Functional outcome of Th1
IFNgamma activates macrophages to kill intracellular bacteria
Functional outcome of IL4
Activates B cells to produce IgE which then work with mast cells and eosinophils. Work well against multicellular parasites.
Type I hypersensitivity
Funcitonal outcome Th17
inducing neutrophil recruitment and clearing of extracellular bacteria
functional outcome of Tfh
isotype switching anf affinity maturations of B cells
functional outcome of Treg
overall just suppressive and inhibit responses of T cells.
