Adaptive response Flashcards
(47 cards)
T cell receptor
2 polypeptide chains of alpha and beta. Similar organisation to Ig light and heavy chain, combination of unique alpha and beta define highly variable complementarity determining region = unique antigen binding site. Always membrane bound via intracellular cytoplasmic tail, and single antigen binding site has less strong attachment - but multiple copies of TCR will bind multiple copies of MHC:antigen complex on opposing cells = multipoint attachment.
Genetic recombination in T cells
Same process of gene rearrangement producing variable region as in B cells, occurs during T cell development in the thymus. Recombination activating genes (RAG) are important in this process. Following antigenic stimulation, no further gene changes occur (no somatic hypermutation), as used for regcognition then mediation of effector functions.
SCID
= Severe combined immunodeficiency
Caused by mutations in differrent genes involved in developiing immune cells. One example is RAAG-deficient SCID. = Autosomal recessive immunodeficiency characterised by lack of circulating T and B cells. Abnormal recombinase means VDJ aren’t successfully combined and hence both B and T arms are totally absent and patients are extremely vulnerable to severe infections in early life.
SCID treatment
The only current possible therapeurics is bone marrow transplant, providing a new immune system for a totally compromised patient. Gene therapy has been successful in some cases, particularly adenosine deaminase (ADA) SCID after a decade of research to find safe restoration of normal purine metabolism and immune function.
Antigen processing
Peptide antigens chopped up inside cells, and then presented on macrophages, dendritic cells or human cells infected with virus. Preserved and displayed non-discriminatively on surface inside MHC complex such that can be recognised by a TCR.
Ligands recognised by TCR
Highly constrained, and specific variations on a structural theme or foreign antigen + MHC protein.
MHC class I
Present intracellular antigens. Intracellular protein degradation, delivered to the ER and bound to MHC-I. Constricted peptide length as must fit into small binding pocket, peptide can only be 9aas in length. If pathogenic, recognised by cytotoxic T cells to help defend against intracellular pathogens.
MHC class II
Present antigens from extracellular pathogens. Molecules from endo/lysosomal degradation are bound to MHC II and presented on the surface. Ends are unrestricted so peptides can have increased length.
T cell co-receptors
CD4 and CD8 assist in TCR recognition of MHC-antigen complex. CD4 binds to MHC-2 at different site to antigen, and CD8 to MHC-1.
Activated CD4 T cells
Effector cells of 5 subtypes = helper cells. Dacilitate macrophage activation to improve their phagocytosis and help B cells.
Activated CD8 T cells
Cytotoxic T cells kill cells infected with virus or other intracellular antigen.
Thymocytes in the thymus
Thymocytes are embedded in the thymic stroma in the cortex and less dense inner medulla.
Dendritic cells enter and populate the medulla + colonisation by some macrophages.
Point of positive and negative selection of different T cell receptors.
DiGeorge Syndrome
Failure of the thymus to develop can result in completeDGS where no T cells are matured = little or no protective immunity. Differing from SCID in that it is to do with the thymus rather than a defect in the haematopoietic lineage. Recent development of thymus transplantation to reconstitute naive T cells and TCR repertoire. Post natal thymic tissue readily available, due to being removed during open heart surgery. Don’t require any immunosuppression considering total lack of immune system.
Expression of CD4 and CD8
Expression of either these is a critical marker of gene expression, eg precursor thymocytes are initially double negative. IL-7 is critical cytokine (secreted by thymic stromal cells), and Notch 1 required to drive T cells through pathway of differentiation. FOllowing gene expression and proliferation, cell expresses both CD4 and CD8 = double positive.
Consequence of lack of productive T cell receptor arrangment
If beta chain gene does not rearrange productively then thymocyte will be triggered to undergo apoptosis and then phagocytosis. If beta chain gene rearranges productively then forms pre-T cell receptor with a surrogate alpha chain.
Positive thymocyte selection
-In cortex of thymus complexes of self-peptides and self-MHC assemble on surface of cortical epithelial cells.
- Contact and test double positive thymocyte alphabeta receptor with self-peptide/self-MHC complex. Binding = positive signal
No positive signal, second change of alpha chain rearrangement, and still none = triggers apoptosis
- The MHC to which the T cell binds is the one to which it will be restricted (eg determines CD4/8 fate).
-Become single positive thymocytes.
Expression of 2 types of TCR
As ‘second chance’ of alpha receptor rearrangement is given, can occur at both copies of the alpha chain locus, so double positive thymocytes can express 2 types of TCRs. So can positively select from one of these which otherwise wouldn’t be chosen.
Negative selection of thymocytes.
Binding too strongly to complexes of self-peptide/self-MHC suggests positive autoreactivity, so negatively selected, engaged by macrophages and dendritic cells and induced to undergo apoptosis.
Exposure to many proteins in thymus
Small population of epithelia cells in the thymus are induced by the transcription factor AIRE to transcribe several hundreds of genes, such as for the protein insulin which otherwise wouldn’t be encountered in the thymus, so proviing central tolerance in the T cell repertoire.
Signals for activation of t cells
- foreign peptide bound to MHC complex interacting with specific TCR.
- Costimulatory molecules such as CD80 and CD86 which are recognised by CD28 receptor on T cell receptor surface.
- Presence of ILs which stimulate proliferation and differentiation.
Autocrine T cell regulation
First two signals induce secretion of IL-2 and also production of a high affinity cell surface receptor for IL-2 which activates intracellular pathwats to stimulate proliferation and differentiation. Only differentiate when several cells respond to antigen in the same location at the same time = spatial and temporal regulation.
Negative feedback of T cell activation
Once activated, a T cell will express a cell surface protein called CTLA-4 which resembles CD28 but binds to costimulators with higher affinity, and then once bound will halt affinity. Experiments show mice with disrupted CTLA-4 genes will die as a result of massive activated T cell accumulation. Also as antigen and cytokine levels fall, effector cells are no longer stimulated and the majority die by apoptosis.
Determination of T cell response produced
Depends on other stimulatory molecules. CD8+ will interact with MHC class I and IFN gamma and then differentiate into cytotoxic T cells. CD4+ will interact with MHC class II. With presence of IL-12 leads to T helper 1 production, stimulating macrophage activation. Presence of IL-4 leads to T helper 2 production, stimulating B cells to produce antibodies - partic IgE to activate mast cells.
T helper 1 cells
Secrete interferon-gamma and TNF alpha to activate macrophages to kill microbes located within their phagosomes.
Also activate cytotoxic T
