Cellular Basis Flashcards
Define immunological tolerance.
- non-responsiveness to specific antigens
- tolerant of self, food, environment
- homeostasis (enhanced tolerance = recurrent infection; defective tolerance = immune response)
What are the 2 methods of gaining tolerance?
- central
- peripheral
Define central tolerance.
- thymic maturation
- based on negative selection of T cells that react to self-antigens presented in the thymus or B cells that react to self-antigens in the bone marrow
What are 3 methods of gaining peripheral tolerance?
- Tregs
- MDSCs
- Clonal anergy
Define regulatory T cells.
suppress the immune response
Define MDSCs.
myeloid-derived suppressor cells = firefighters
- kill activated T cells to prevent further stimulation
- recruited to a site of infection by inflammatory cytokines (IFNg)
Define clonal anergy.
T cells do not induce an immune response because they are not activated in the proper way. This can be due to a lack of appropriate co-stimulators
Define AIRE.
autoimmune regulatory element (?)
- transcription factor that allows thymic mTECs to produce non-thymic self peptides to test for autoimmunity
- those T cells with high affinity => apoptosis
- those T cells with low affinity => leave as naive T cells
- those T cells with intermediate affinity => become nTregs in the Hassall’s Corpuscles
Describe Treg differentiation in the thymus.
- those T cells with intermediate affinity to self-antigens=> become nTregs in the Hassall’s Corpuscles
- induction of Foxp3
- requires IL2
Describe what a loss of AIRE leads to.
APS or APECED
- loss of central tolerance
- lots of autoimmune disorders
- particular autoimmunity against endocrine organs
Describe the function of MDSCs.
- initially found to infiltrate solid tumors; now found in adipose cells
- activated by IFNg
- produce anti-inflammatory cytokines
What are MDSCs used for in treatment?
- anti-MDSC antibodies used in anti-tumor treatment (suppression of MDSCs => enhance immune response)
- MDSCs used in autoimmune disorders or transplants
Define nTregs.
- generated in the thymus
- suppress other T cells
- express foxp3 and CD25 (IL2Ra)
- antigen-specificity is limited to self-antigens (can’t be used to suppress immune responses to food/environment)
Define iTregs.
- generated in peripheral lymphoid organs
- antigen-specificity includes food, environment, commensal bacterial peptides, and tumors
- requires both TGFb and IL2, and Foxp3 expression
- inhibited by IL6
- induced by APCs in the mucosa
- cofactors required include Vitamin A and Vitamin D
Define Tr1 cells.
- induced by TGFb and IL27
- do NOT express Foxp3
- produce IL10
- if there is lots of IL10 in the environment, they can be induced
- IL10 is upregulated by Vitamin D => increased Tr1 generation
Describe IPEX.
immune dysregulation polyendocrinopathy enteropathy Xlinked (?)
- lack of peripheral tolerance
- lack of Foxp3 => no Tregs
- systemic autoimmunity
- leads to death if not treated with bone marrow transplant within first year
What causes clonal anergy?
- lack of CD28 costimulation by CD80/86 on APCs
- causes partial activation that leads to degradation of signaling molecules required for activation
- cell can no longer be activated
- therefore, when an antigen is presented by a tumor or a regular cell, the T cell will become anergic (this is good - if antigen is on self; bad if antigen is on tumor)
What is CTLA-4?
- expressed after a T cell is already activated to prevent further stimulation
- competes with CD28 for binding to B7 (CD80/86)
- has higher affinity for B7 (Basically a CD28 cockblocker)
- recruits suppressor molecules for TCR; blocks antigen activation
What roles does CTLA-4 play?
- natural: increased expression after T cell activation to prevent runaway T cell proliferation and stimulation
- immune homeostasis (knockout leads to autoimmune disorders)
- Tx for cancers (anti-CTLA4 antibodies causes enhanced immune response)
- Tx for autoimmune disorders (CTLA-4-Ig inhibits CD28 from the outside of the cell by binding to B7 on the T cells)
Describe the mechanism for how MDSCs work.
- immune response typically involves Th1 and CD8, which produce IFNg
- IFNg is proinflammatory and recruits MDSCs to the site of infection
- IFNg activates MDSCs to differentiate into suppressor cells
- MDSCs generate NO (apoptosis) and arginase (cell cycle arrest) to suppress T cells
Compare Tregs and MDSCs.
- MDSCs are firefighters (recruited to site), while Tregs are police officers (constantly present)
What is the role of IL2?
maintenance and induction of nTregs
What is the role of the Hassall’s corpuscle?
- located in medulla of thymus
- location of nTregs differentiation
- provides TSLP (thymic stromal lymphopoietin) for nTreg differentiation
What is unique about TGFb being involved in the iTreg differentiation process?
- typically, TGFb is proinflammatory, when in conjunction with IL6 (forms Th17)
- however, in the presence of IL2 => iTregs
What is the relationship between Th17 and iTregs?
opposite effects
What is the effect of loss of TGFb?
- loss of effector cells (Th17)
- loss of regulatory cells (iTreg)
