Jitt # 6 Reading Chp. 15 315-319 Flashcards
Immunological Tolerance
Defined as an unresponsiveness to an antigen that is induced by previous exposure to that antigen
Self-tolerance
tolerance to self antigens
autoimmunity/autoimmune disease
Immune reactions against self antigens that result in diseases
In healthy individuals, why aren’t self antigens recognized by lymphocytes?
Lymphocytes that recognize self antigens early in development are killed or inactivated or the specificity of these lymphocytes is changed
Central Tolerance
Maturation that occurs in the bone marrow and thymus for B cells and T cells respectively. Maturation occurs to ensure that maturing lymphocytes do not react to self. It is important to note that there are not many (if any) non-self antigens in central lymphoid organs. Peripheral lymphoid organs house non-self antigens.
Peripheral Tolerance
Is induced when mature lymphocytes recognize self antigens and die by apoptosis, or become incapable of activation by re-exposure to that antigen.
Treg
Regulatory T Cells, actively suppress self antigen-specific lymphocytes. Suppression occurs in secondary lymphoid organs and in nonlymphoid tissues; Arise from CD4+ lineage
How does the anatomy effect immunological response?
Some barriers, testes and eyes, do not interact with lymphoid receptors. Some other areas of the body do not as well, but it is not well understood.
Why is it important to understand tolerance in the context of CD4+ T cells?
Because not only are CD4+ important in cell mediated immunity, but they also activate humoral facets of immunity.
Deletion/Negative selection
The process by which T cell receptors who recognize antigens with high avidity are deleted.
Where does negative selection for T cells occur?
Occurs in double positive T cells in the thymic cortex and newly generated single-positive T cells in the medulla.
Antigens in the thymus
Antigens in the thymus are typically only those present in certain peripheral tissues. Important for ensuring non-reactivity to self
AIRE
Autoimmune regulator protein; Protein that is responsible for the presentation of peripheral tissue antigens. Secreted by thymic medullary epithelial cells; important in the process of negative selection
APS1
Autoimmune polyendocrine syndrome I; multiorgan autoimmune disease caused by a mutation in the genes encoding for AIRE; Characterized by injury to the endocrine organs parathyroids, adrenals and pancreatic islets.
What happens to some self reactive CD4+ cells that recognize self antigens in the thymus?
They differentiate into regulatory T cells specific for these antigens; they leave the thymus and inhibit against self reactive antigens in the periphery.
What are the three mechanisms of peripheral tolerance?
Anergy, suppression by regulatory T cells and deletion
Anergy
Functional unresponsiveness; Mature CD4+ T Cells that are exposed to an antigen in the absence of co-stimulation or innate immunity may make the cells incapable of responding to that antigen; prolonged signal 1 ( antigen recognition) without costimulator confers anergy.
What are the three costimulators?
B7-1, B7-2, CD28
Ubiquination and TCR in self-tolerance
Receptors that recognize self-antigens are ubiquinated and thus targeted for degradation by proteasomes or lysosomes; Cbl-b ubiquitin ligase important in T cells.
DiGeorge Syndrome
Congenital absence a thymus. Results in low numbers of mature T cells in the circulation and peripheral lymphoid tissues.
Thymocytes
Developing T Cells in the Thymus
Which type of T cells mature into CD4+ or CD8+ in the thymus?
alpha/beta T cells
What functions do DCs and epithelial cells play in Thymocyte maturation?
epithelial cells and DCs express MHCI/II in the thymus. Important for Thymocyte maturation.
What function do thymic stromal cells, along with epithelial cells play in lymphocyte maturation?
They secrete chemokines and cytokines that are important for lymphocyte development. IL-7 is a growth factor. CCL21 and CCL19 are both recognized by CCR7 and mediate the movement of thymocytes through the thymus.
Pro T Cell Stage
(CD8-, CD4-); Rag 1/2 first expressed here; Db to Jb rearrangement; Vb to DJb rearrangement to transition to Pre-T stage
Pre T Cell Stage
Officially a Pre T Cell after Vb to DJb rearrangement; and expression of Pre-TCR.
Pre TCR
Made up of TCR beta chain, invariant Pre T-alpha chain, CD3 and zeta proteins; mediates the selection of a correctly rearranged TCR B chain; Pre TCR mediates survival of T cell and contributes to proliferation; also contributes to the initiation of alpha chain rearrangement and the transition of double negative to double positive stage of thymocyte development; also has signals that limit other B chain to rearrange (allelic exclusion) along with the production of the Pre TCR b protein
Double Positive Thymocyte stage
Occurs after Pre TCR stage. CD4+ and CD8+; CCR7 chemokine receptor activation (aids in the migration of thymocytes from the cortex to the medulla); Chemokines secreted by stromal cells; rearrangement of TCR alpha chain and gene expression; TCRab heterodimer expressed (caused by after TCR a expression); now available for positive selection.
Late Pre T Stage
2nd wave of Rag genes expressed; TCRa rearrangement; Rag1/2 turned off by TCRab heterodimer during positive selection;
TCR a rearrangement
Occurs in late Pre-T cell phase. Only V to J rearrangement; no allelic exclusion for alpha chain. May express two alpha chains; failure to rearrange alpha chain leads to no positive selection; results in deletion of TCR delta locus (cell no longer capable of being gamma delta T cell)
Single Positive Thymocytes
Have either CD4+ (produce CD40 ligand) or CD8+(produce cytotoxic compounds)
Positive TCR Selection
Occurs when a thymocytes TCR binds to self-peptide & self MHC with low avidity. Selects for its survival; non-recognition leads to apoptosis; MHCI/II-CD4+/CD8+ designation made here.
Negative selection
The process by which thymocytes whose TCRs bind strongly to self peptide antigens in association with self MHC molecules are deleted. Eliminates autoreactive T cells.
Which type of cells are involved in positive selection? Negative Selection?
Cortical epithelial cells (positive selection); DCs and medullary epithelial cells (negative selection)
What is the role of CCR7 in thymocyte maturation?
CCR7 is a receptor for CCL21 and CCL19 (chemokines) which mediate the migration of double positive T Cells to the thymic medulla.
Bim
Pro-apoptotic protein; TCR signaling causes induction of protein
Pro-T Cell
Tdt expressed, Rag1/2 expressed in late pro- T; No TCR expression; DNA unrecombined; Cell surface markers c-kit, CD44+/CD25+; (No response to antigen)
Pre- T Cell
Recombined B chain gene; VDJ rearrangement; B chain mRNA; Pre - T receptor (B chain/ pre-T alpha); cell surface markers CD44-;CD25+; c-kit. (no response to antigen)
Double Positive T-Cell
Recombined B, a genes; [V(D) J-C]; B and A chain mRNA; membrane AB TCR; Cell surface marker CD4+, CD8+, TCR/CD3’˚; Response to antigen (positive and negative selection)
Single Positive (Immature T-Cell)
Recombined B, a genes; [V(D) J-C]; B and A chain mRNA; membrane AB TCR; Cell surface marker (CD4+/CD8-) or (CD4-/CD8+) TCR/CD3hi;
Naive mature T Cell
Recombined B, a genes; [V(D) J-C]; B and A chain mRNA; membrane AB TCR; Cell surface marker (CD4+/CD8-) or (CD4-/CD8+) TCR/CD3hi; Response to antigen: proliferation and activation in the periphery
Nude Mouse
A mouse that does not have a thymus.
