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Flashcards in Immunoregulation Deck (20):

Activation and Differentiation of Naïve TH cells

Activation and differentiation of naïve TH cells requires three independent signals delivered by the same APC

Signal 1: ligation of TcR (and CD4 or CD8 co-receptors) to MHC-peptide on APC

Signal 2: co-stimulatory surface molecules such as B7 (B7.1 = CD80 and B7.2 = CD86) on APC binding with CD28 on T cells

Signal 3: cytokines from the APC or tissue environment at the time of antigen recognition


Regulation of Immune Responses by CD4+ T cell Subset-Derived Cytokines

Differential release of cytokines by CD4+ T cell subsets control:

Humoral vs. Cell-mediated immunity
IFN-g producing TH1 cells (promoting CMI and opsonizing Ig) and IL-4 producing TH2 cells (promoting nonopsonic IgG, IgA, IgE) are counter-regulatory cells (mutually antagonistic or suppressive).

Tolerance to autoantigens or nonself antigens (commensal microbes, pollens, food antigens)
Induced regulatory T cells (Treg) exhibit immunosuppressive (regulatory) function after unique stimulatory conditions
Natural suppressor CD4+CD25+ T cells (nTreg) develop in the thymus.


Dendritic Cell Control of Pathogen-driven T cell Polarization

Once immature dendritic cell sees Ag, it matures based on the TLR response to PAMPs and tissue factors

Then the dendritic cell secretes cytokines and co-stimulatory factors that influence the determination of which T helper subsets are made (Th1, Th2, Th17, or T reg)



Secretes IFN gamma, TNF alpha, IL-2, and IL-6
Promotes CMI and opsonizing Ig

INF gamma promotes:
macrophage activation and IgG production
response to intracellular microbes
role in autoimmune disease and tissue damage with chronic infections

If TH1 cell presenting to macrophage via INF gamma, then causes macrophages activation and enhanced microbial killing
If TH1 is presenting to B cell via IFN gamma, then this promotes the B cell via INF gamma to class switch from IgM to IgG and complement binding and opsonizing



Secretes IL-4, IL-5, IL-10, and IL-13
Promotes non-opsonizing IgG, IgA, and IgE

IL-4, IL-5, and IL-13 promotes:
mast cell, macrophage, and eosinophil activation
IgE production
response to Helminthic parasites and allergic diseases

IL-4 to B cells = IgG to IgE switching
IL-4, IL-13 = intestinal mucus secretion and peristalsis; alternative macrophage activation for enhanced fibrosis/tissue repair
IL-5 = eosinophil activation



Secretes IL-17A, IL-17F, TNF-alpha, and IL-22
neutrophilic and monocytic inflammation
defense in extracellular bacteria and fungi
role in autoimmune and inflammatory diseases

IL-17 = activates leukocytes and tissue cells to produce chemokines, TNF, IL-1, IL-6, and CSF to cause inflammation and neutrophil response as well as antimicrobial peptides
IL-22 = activates tissue cells for antimicrobial peptides and increase barrier function



Secretes IL-10 and TGF beta
Exhibits immunosuppressive (regulatory) functions
Induced by non-infectious agents and Treg turns off the immune system and maintains peripheral tolerance to prevent unnecessary chronic/acute inflammation


Th0 Differentiation

IL-12, IFN gamma = TH1

IL-4, IL-2 = TH2

TGF beta, IL-6 = TH17

TGF beta, IL-2 = Treg

*signals are from dendritic cells to Th0 to develop into these respective subsets of T helper cells


Absence of Infection Signals

In absence of infection (absence of IFNg or IL-12), high TGFb promotes differentiation of Treg that suppress Th1 or Th2 responses to normally presented self antigens via Treg release of TGFb and /or IL-10.


Early Infection Signals

Early in infection, high IL-6 and IL-23 release combine with TGFb signals to induce TH17 differentiation. TH17 cells secrete IL-17 (induce epithelial, endothelial, fibroblast release of chemokines that promotes neutrophil recruitment) and IL-22 that induces b-defensin production.


Late Infection Signals

Pathogen-induced cytokines (via TLR activation) predominating in later stages of infections drive differentiation of Th1 and Th2 subsets.

Common extracellular bacteria: dendritic cell pick up these it will release IL-12 and interact with NKC and produce INF gamma = indicate inflammatory stimuli and T cell will make TH1, which major product is INF gamma to continue opsonization and inflammatory responses

There are certain types of microbes and allergens that may produce high levels of IL-4 production to make TH2, which make IgE (for parasites and hypersensitivity/ allergic reactions)


Parasitic Worms

Worms: can stimulate NKTC that have surface markers that are like NKC and have T cell receptors, and recognize glycolipids in local tissues and make lots of IL-4 and this causes T cells to go to TH2
TH2 secretes IL-4, which causes Ig class switching of B cells to E class to promote cytotoxic reactions to parasites like mechs to expel the worms and also hypersensitivity reactions


Control of Activated T cells

CTLA-4 expression replaces CD28 during later stages of T cell activation to provide a negative signal for further T cell expansion

Activation-induced cell death (AICD). Activated T cells (both CD4+ and CD8+) express Fas and/or FasL during the later stages of immune response when antigen diminishes. FasL-Fas interactions induce apoptosis to eliminate most of the clonally expanded, specific effector T cells that are no longer needed. Memory T cells (Fas-) are spared

If lymphocytes kept proliferating, it would be bad so Ag driven process = lymphoproliferative diseases otherwise


Regulation of Immune Responses (IR) by Antigen Concentration

Too low or too high a dose of antigen will be non-immunogenic or toleragenic respectively.

Continuing IR are antigen-driven and decline in parallel with antigen concentration (antigens, costimulators, and cytokines provide survival signals that prevent apoptotic pathways)
Soluble and readily degraded and excreted antigens are poorly immunogenic
Aggregated or persistent antigens are more immunogenic
Some “adjuvants” promote immunogenicity of materials by prolonging immunogen halflife in vivo


Antibody Feedback Inhibition and Anti-Idiotype Ab

Antibody feedback inhibition of IR
B cell binding of antigen-antibody complexes via BCR and FcgRIIB-1 simultaneously delivers a negative signal to B cells
BCR signaling is inhibited by FcgRIIB-1 associated ITIMS (immunoreceptor tyrosine-based inhibitory motifs)
Once you made many Ab/ complexes, it provides B cell with negative feedback to turn off; B cells also have Fc receptors and immune complexes can cross link and send negative signal

Anti-idiotype antibody (anti-antigen receptor)
anti-idiotype antibody mimics the 3-D shape of the original antigen (an internal image of external antigen) and can positively or negatively regulate lymphocyte activation.


Genetic Control of Immune Responses

MHC II genes are also known as immune response genes
MHC genes are polymorphic (multiple alleles) and differentially inherited
**T cell responsiveness to any specific peptide determinant is dependent on inheritance of particular MHC alleles.
Susceptibility to many infectious and immune mediated diseases correlates with tissue type (inherited MHC) because of the influence of MHC genes on immune responses.

Gene polymorphism and differential inheritance of variant forms of many other immune molecules (receptors, cytokines, etc) correlates with variations in disease susceptibility



Inheritance patterns for inflammatory conditions regulated by immune genes within MHC, especially MHC II loci
T cells only see peptides presented with MHC molecules, you inherit MHC set of genes (4-6 different ones) and each MHC produce multiple peptides and bind many, but possible that none of the inherited MHC molecules can bind so if exposed to one of these peptides, you are immunologically blind to that determinant
Usually does not cause any deficiency in immune response because you make polyclonal response because multiple peptides make an immune response, but in certain disorders, if that peptide is critical for a response and you lack that MHC to recognize that peptide, then compromised and susceptible to that disorder; if peptide is target to autoimmune disease, then if you inherit MHC to present that peptide, then you have the susceptible to getting that disorder
T cell response to any peptide is dependent on inheritance of the MHC allele


Immunological Memory

Memory = the ability of the adaptive immune response to respond more rapidly and effectively to pathogens that have been encountered previously and prevents them from causing disease

Memory responses = secondary immune responses

Memory maintenance does not require repeated antigen exposure due to long-lived antigen-specific memory B and T cells

T and B memory cells that persist for life without repeated Ag exposure
Some reservoir of Ag sometimes for preservation, but not common via follicular dendritic cells


Follicular Dendritic Cells

Follicular dendritic cells (FDC) may serve as a reservoir of antigen (trapped as immune complexes bound to FDC membrane FcR and CR) for long term re-stimulation of memory cells


Immunological Memory Maintenance

T memory cells develop within 5 days after primary antigen exposure, B memory a few days later

Maximal B cell memory at 1 month

Antibody secretion is sustained by plasma cells in bone marrow (months to years after initial response)

Plasma cells can live for years (in marrow) and there is threshold of specific Ab to elicit protection of the disease, but over time that Ab level will decrease below protective level, and so periodically need to get booster shots to increase plasma cells to protect again