immune tolerance Flashcards
what is immune tolerance
immune tolerance: prevents undesirable immune responses e.g to self antigens
what are types of immune tolerance
central tolerance, peripheral tolerance
where does central tolerance occur
central tolerance occurs in primary lymphoid organs, peripheral tolerance occurs later once cells have left lymph system
central tolerance occurs in bone marrow for B cells and thymus for T cells
if an immature B cell in bone marrow binds to self antigen it either can undergo receptor editing (changes specificity) or it can undergo deletion (it dies)
when T cells are developing they do not express either CD4 or CD8 (double negative thymocytes), they then express both CD4 and CD8 where they are called a double positive thymocyte
what is positive selection
if the thymocyte recognises peptide with MHC class 2 it will downregulate CD8 and will become a CD4 cell
if the thymocyte recognises peptide with MHC class 1 will downregulate CD4 and becomes CD8 cell
this process is called positive selection since the T cell must be able to recognise self MHC, it occurs in the thymic epithelial cells in the cortex of the thymus
what is negative selection
if a thymocyte cannot recognise either apoptosis occurs (death by neglect)
thymocytes that have strong recognition of either MHC class undergo apoptosis since they may be dangerous, this is negative selection which occurs in the dendritic cells of the medulla of the thymus
positive selection occurs then negative selection
what is AIRE
AIRE: autoimmune regulator; transcription factor in the thymus that switches on expression of tissue specific antigens (e.g insulin), AIRE in used in central tolerance to prevent self reactive T cells
what is peripheral tolerance
since central tolerance mechanisms are not perfect there are still T cells which have potential to be self reactive, peripheral tolerance helps prevent this
peripheral tolerance is mediated by cell intrinsic mechanisms and cell extrinsic mechanisms (regulatory T cells)
what are 2 types of peripheral tolerance
cell intrinsic and cell extrinsic
what are cell intrinsic mechanisms of peripheral tolerance
ignorance: if a self reactive T cell remains “ignorant” of its antigen it does not cause reaction (T cell does not encounter antigen)
Anergy: t cells require antigen to be presented via MHC, requires costimulatory signal via CD28, if no CD28 stimulation occurs cell becomes anergised, meaning antigen specific unresponsiveness meaning it cant form a response, since resting APCs (antigen presenting cells) do not provide CD28 signal
phenotypic skewing: if CD28 costimulatory signal occurs as well and T cell is activated, instead of differentiating to a way which would cause harm (to Th-17), they differentiate another way in which functional tolerance is preserved
apoptosis: T cell recognises its self antigen and undergoes apoptosis
what are cell extrinsic mechanisms of peripheral tolerance
Regulatory T cells, express Foxp3 and CD25 (component of IL-2 receptor), they repress immune responses
shimon sakaguchi: took mice with no thymus (no T cells) and reconstituted some with all T cells and some with CD25-depleted T cells. The ones lacking CD25 became autoimmune
regulatory T cells; secrete inhibitory cytokines (e.g IL-10 and TGFbeta), use regulatory protein CTLA-4 to modify antigen presenting cells (block or remove costimulatory ligands), bind and consume IL-2 (a growth factor for T cells).
controlling tolerance at T cell point is important since helper T cells recruit cytotoxic T cells, macrophages and B cells
