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34 Cards in this Set

  • Front
  • Back
What constitutes immune "tolerance"?
Discrimination between
-non-self and self
-harmless and dangerous
-Attack focused on dangerous non-self

If the antigen is not dangerous then the response may be more dangerous than the original antigen.
What are the response cell intrinsic regulatory mechanisms of immune cells?
Ignorance
Activation induced cell death
Anergy
What are the response cell extrinsic regulatory mechanisms of immune cells?
Regulatory (suppressor) T cells
What is AIRE?
Autoimmune regulator:
-Gene highly expressed in thymic epithelium
-Encodes a transcriptional activator
-Induces expression of "ectopic" self proteins
-Pancreas, retina, ovary specific
Describe how the thymocyte avidity profile is "molded"
The T cells that leave the thymus will have low-moderate aviditiy with self. If they have 0 avidity, they don’t make it through positive selection. If they have high avidity they are eliminated in negative selection. There is a wider range of avidities with foreign antigens, ranging from no avidity to high aviditiy.
What is APECED?
-Clinical condition from mutation in AIRE
-Autoimmune attack on multiple endocrine structures (thyroid, parathyroid, adrenals, beta-islets, gonads), vitiligo, alopecia
What is affinity?
Binding strength of one receptor to one ligand
What is avidity?
Aggregate binding strength of multiple receptors on one surface to ligands on another
How does TCR avidity contribute to T cell activation?
High avidity - Activated at low Ag concentrations
Moderate avidity - required higher Ag concentrations
Low avidity- largely "ignorant"
What is ignorance?
Low TCR-Ag/MHC avidity and/or low antigen abundance result in failure to produce signal 1
What causes clonal deletion?
High antigen density - persistent TCR triggering in the absence of costimulation -> AICD. With persistant signaling, FAS is upregulated on the surface of the cell. If you repeatedly trigger the CD4 cell you get the cell to express its own FAS. Now you have FAS and FAS ligand on the same surface.
Describe activation-induced cell death (AICD)
-Elimination of clonally expanded effector T cells in the "terminal phase" of an antigen response
-From persistent or repeated TCR triggering
-Cell death is apoptotic - largely fas mediated
-fas is upregulated following T cell activation
-anti-fas or anti-fasL antibodies inhibit AICD
-fas- or fasL-deficiency -> lymphoproliferation/autoimmunity

-Inappropriate AICD may result in pathological T cell loss in HIV, EBV, VZV
What is CTLA-4
CTLA-4 is one of the main ways that we turn off the T cell response. It is expressed on activated T cells. It binds to CD80/86 with higher avidity than CD28. It delivers an inhibitory signal to the responder T cell.

Since CTLA-4 has a higher avidity for CD80/86 than CD28 it will tend to outcompete the CD28. Hopefully by this time you have fought off the infection by this point, so there is not much antigen around. The expression of CTLA-4 removes the costimulatory signal and the result is clonal contraction.
What is CD25?
The IL-2 receptor alpha chain. It is paired with the beta and gamma chains to make a high affinity IL-2 receptor.
What are the different types of Tregs?
CD4+/CD25+ Tregs
-Natural or thymic - develop in the thymus
-Adaptive or induced - conversion of naive CD4s in the periphery

Other CD4+
-Th3
-Tr1

CD8+ - also described but less well established
Describe the CD25 on Tregs
t can serve as a marker for Treg cells, but it is on every activated T cell. The difference is that Tregs express it throughout life, while the other effector T cells just have a proliferative burst when they are activated and then CD25 is downregulated again.
Describe CD4+/CD25+ Tregs
-10% of circulating CD4+ cells bear CD25
-Upon triggering with CD3/CD28 crosslinking in vitro ->
-no proliferation
-no secretion of IL-2, IL-4, or IFN-gamma
-contact-dependent inhibition of local "responser" T cells
-Capable of self-renewal in vivo
-Constitutively express CTLA-4
-Dependent on IL-2 for maintenance of regulatory phenotype or for survival
-IL-2 deficiency and CD25-deficiency are both associated with autoimmunity.
Describe Treg function
-Require activation via TCR to implement suppression
-Once activated, suppression of other cells is not MHC restricted
-Activated Treg's mediate "bystander" suppression
-Optimal suppression requires cell contact
-Target include CD4+ and CD8+ T cells, B cells, macrophages, NK cells, mast cells
-There is a resting state where they don’t suppress anything. When their TCR is crosslinked, they become suppressor cells.
Describe Tregs of thymic origin
-The majority (>80%) of circulating Treg's are of thymic origin
-The nTreg career choice occurs late in thymic development
-CD4 single positive stage
-After positive and negative selection, but before exit
-Requirements:
-TCR triggering by self Ag
-CD28 ligation by CD80/86
-IL-2 stimulation (also IL-15)
-Decision event: activation of FoxP3
-Treg transcriptional program regulator
What does FoxP3 do?
-FoxP3 represses TCR-triggered IL-2 transcription, induces CTLA-4 and CD25 transcription
-FoxP3+ function is stable in nTreg's - transferrable by adoptive transfer
-Mouse: FoxP3+ T cells are >90% CD4+/CD25+ and functionally suppressive.
-In humans, FoxP3 is expressed transiently in activated naive T cells
What do nTregs recognize?
-The natural target antigens of Treg's are unknown.
-TCR receptor usage shows only ~20% overlap between nTreg's and effector CD4+ T helpers.
-They may be recognizing self with not enough avidity to be deleted, but not enough for your average CD4 effector cell thus letting them travel down the Treg route. They arent just plucked out randomly, there is something about their TCRs that makes them go down this direction.
How do inducible Treg's arise in the periphery?
-Naive CD4+ T cells -> CD4+CD25+FoxP3+ under the following circumstances:
-TCR X-linking in presence of TGF-beta
-Suboptimal antigen presentation
-Slow infusion low dose soluble antigen
-Injection of antigen targeted to DCs
-Fusion of Ag with anti-DC antibody

Requirements:
-CTLA-4
-IL-2
-Relative lack of CD28 co-stimulation

If you crosslink TCRs in the presence of TGFbeta there is upregulation of CD25 and FoxP3. These cells can also be created through suboptimal antigen presentation. If the antigen is targeted at the DC, then the DC will take up the antigen and present it. There is not a lot of costimulation. This can lead to the formation of a suppresor population.
Describe the tolerogenic environment in GALT
-Lamina propria DCs balance Treg vs Th17
-Normally low levels of costimulation (CD80/86)
-Secrete TGF-beta and retinoic acid
-RA reduces sensitivity of naive CD4+ T cells to inflammatory cytokines: IL-6, IFN-gamma, IL-17
-With tissue damage/pathogen invasion
-Increase production of IL-6
-Convert from Treg generation to Th17 generation
What is the role of retinoic acid in the tolerogenic environment in GALT?
Retinoic acid plays an important roll in downregulating the sensitivity of a naïve T cell to various inflammatory cytokines. With damage, the increase in IL-6 can overcome this desensitivity.
How do you convert Tregs to Th17?
Large amounts of IL-6
How do you convert Th17 to Th2?
IL-4
What allows the guy to tolerate LPS more than other areas?
Retinoic acid
What is the origin of Tregs in the thymus?
In they thymus, DP thymocytes can become CD8 cells or CD4 cells. Just before exiting some number of them will recognize antigen in the context of class I with CD80/86 and they will get IL-2 and differentiate down a T-reg pathway.
What are the origins of inducible Tregs
In the periphery, there are FoxP3 negative CD4 Tcells, in the presence of suboptimal stimulation and in the presence of TGF-beta can become Tregs. They need IL-2 and they will then suppress both CD4 and CD8 responses. In the GALT there are special DCs that make TGF-beta on a tonic low level. It also makes retinoic acid. Those two agents together with a little receptor crosslinking leads to the generation of a FoxP3+ Treg cell and suppression of CD4 and CD8. The thymic Tregs are relatively permanent Treg. They are terminally differentiated. The inducibles can be converted back to a Th17 or beyond that in the right cytokine environment. The perminant Tregs are methylated at certain genes while the inducibles just have certain transcription factors.
What are the differences between thymic Tregs and inducible Tregs?
The naïve T cell population can give rise to either an effector cell, a FoxP3+ Treg, or another type of cell. Thymic Tregs arise in the thymus, while the inducibles can arise anyplace, particularly in the gut. Costimulation: CD28 for thymic cells and CTLA-4 for inducible. TGF-beta is required in the periphery, but it is unclear if it is required in the thymus. In the thymus you need IL-2, though IL-15 can substitute. In the periphery you need IL-2, there is no substitution. In the thymus, specificity is gained through self-peptides. In the periphery the antigen that is triggering the cell can be anything. One ways tumors get around the immune system is that they cause the development of Tregs that shut down the immune response against the tumor.
What are the direct suppression mechanisms of Tregs?
IL-10 and TGF-beta are made by Tregs and can lead to cell cycle arrest. Another proposal is that they bind up all of the IL-2 in the environment. They may have their high affinity IL-2 receptors expressed all the time, depriving the effector cells of IL-2 leading to apoptosis of the effector cell. Some Tregs have granzyme in their cytoplsam, so they may lyse other cells. There are other molecules expressed on Tregs that are good at shutting down the cell cycle. The most important mechanism is the secretion of IL-10 and TGF-beta.
What are the indirect suppression mechanisms of Tregs?
There is also indirect suppression through a Treg interacting with a DC. CTLA-4 may interact with the DC cell causing it to lower its costimulation, reducing levels of CD80/86. There is also a protein that can bind to MHCII reducing its presentation. There is an ATPase on the Treg cell. ATP is an inflammatory signal, so if you eliminate the ATP in the environment you decrease the inflammatory signal. NRP-1 in the environment can cause a long interaction between the Treg and the APC. The idea is that you surround the APC with Tregs and the effector cells cant get the stimulation that they need.
How do you override Treg suppression?
Treg suppression is overridden if there is a great deal of costimulation. Tregs are good at suppressing moderate stimulatory signals, but not great at suppressing strong signals.
How are antigen specific CD4+CD- T cells with regulatory effects generated under specific circumstances?
-Oral administration of antigen -> TGF-beta-secreting CD4+ T cells termed Th3 cells

-Stimulation of CD4 T cells with antigen in vitro in the presence of IL-10 yields a regulatory T cell that secretes predominantly IL-10, and some TGF-beta (termed Tr1 cells)
-Neither of these express FoxP3