Differentiation of T-cells
- in secondary lymphoid tissue
- into CD8 cytotoxic T cells and CD4 TH1, TH2, and TH17 cells
naive T-cells vs effector T-cells
-effector T-cells can travel to infected tissue and involves changes in cell-surface molecules
L-selectin
-permits naive T cells to gain entry to lymph nodes from the blood
VLA-4
-will bind to VCAM-1 of endothelial cells of blood vessels at inflammatory sites so it halts passing effector T cells and direct them to enter the infected tissue
CD2 and LFA-1 on Tcell in infected tissue
-effector T cells express two to four times more CD2 and LFA-1 makes them more sensitive than professional antigen-presenting cells to the smaller amounts of ICAM-1 and LFA-3 on most tissue cells
Effector CD4 T cells
do not directly attack the pathogens that cause infection, but help other cells of the immune system to achieve that goal
Criteria in differentiation of helper CD$ T cells
the tissue of origin of the activated dendritic cell, the nature of the pathogen, and the innate immune response made against it will promote the differentiation
TH1
- help macrophages respond to intracellular bacterial infections and viral infections
- differentiation is controlled by the T-bet transcription factor
TH17
- help neutrophils respond to extracellular bacterial and fungal infections
- differentiation is controlled by the transcription factor RORγT
TH2
- help eosinophils, basophils, mast cells, and B cells respond to parasite infections
- Differentiation caused by GATA3 transcription factor
TFH
- responsible for the activation of naive B cells and their differentiation into antibody-producing cells
- differentiated by the Bcl6 transcription factor
regulatory T cells
- control and limit the activities of other types of effector CD4 and CD8 T cell
- differentiated through FoxP3 transcription factor
Effector T cell signaling
- signals coming from the T-cell receptor and co-receptor are sufficient to activate effector T cells. able to recognize antigens on all cells that express MHC class II molecules
- signals coming from the T-cell receptor and co-receptor induce anergy in naive T cells. activated only by recognition of antigen on dendritic cells
molecules that mediate T-cell effector functions
- cytokines: that alter the behavior of target cells
- cytotoxic proteins/cytotoxins: kill the target cells
Cytokines
- signal for Intracellular signals that induce changes of gene expression
- autocrine action: cytokines can amplify an immune response
- paracrine action: cytokines provide communication and cooperation between different cell types in the immune response
Cytotoxins
- granzymes: family of five serine proteases
- perforin: membrane-disrupting protein
- serglycin: proteoglycan
- granulysin: detergent-like protein that associates with membranes
Cytokines and JAK-STAT pathway
- cytokine receptors are bound to JAK, presence of cytokine allows for formation of receptor, then cytokine binds and receptor is phosphorylated, then STAT binds JAK and becomes phosphorylated, phosphorylated STAT then goes to DNA to change gene expression
- Using JAK-STAT pathway enables the target cells to respond rapidly to stimulation by cytokines which activated transcription of genes for adaptive immune response
Effector TH1 and macrophages
- how do they come together?
- how does it help macrophage
- signals?
- importance of delivery mechanism
- antigen receptor of a TH1 cell recognizes its antigen on a macrophage surface, the TH1 cell and the macrophage form a conjugate pair with a synapse
- causes phagosomes containing captured pathogens fuse more efficiently with lysosomes and increased synthesis of potent microbicidal agents such as oxygen radicals, nitric oxide (NO), and proteases
- primary signal is provided by IFN-γ, the characteristic TH1 cytokine, when it binds to the IFN-γ receptor on macrophages. and secondary signal is delivered by CD40 ligand, a membrane-bound cytokine of the TH1 cell that binds to its receptor, CD40, on the macrophage which induce changes in gene expression
- newly made cytokines are translocated to the endoplasmic reticulum of the TH1 cell and then delivered by secretory vesicles to the synapse with the macrophage which allows for immune response to be focused on where it is needed and prevents unnecessary damage and disruption to healthy tissue
TFH cells and antigen presenting B cells
- pathogen-specific TFH cell surveys these antigen-presenting naive B cells, searching for the peptide:MHC class II complex that is the ligand for its T-cell receptor, TFH-cell receptor binds its specific antigen on a naive B cell, the two cells form a cognate pair and a synapse , TFH cell now synthesizes CD40 ligand, which binds to CD40 on the B cell starts the developmental pathway by which the naive pathogen-specific B cell proliferates, differentiates, and ultimately matures into an antibody-secreting plasma cell.
M. leprae infections and immune responses
- what is leprosy?
- 2 types
- how does type 1 work? type 2?
- Leprosy: persistent infection of the vesicular system of macrophages with Mycobacterium leprae
- effector CD4 T-cell response polarized TH1 or TH2
- TH1-biased respons:the cytokines made by the TH1 cells help the infected macrophages to suppress the growth and dissemination of the bacteria; disease progresses slowly and patient does NOT die
- TH2-biased response: large amounts of pathogen-specific antibodies are made, they are ineffective against the bacteria hiding inside the macrophages. By growing unchecked, the bacteria become disseminated to other sites in the body, causing gross tissue destruction, which is eventually fatal.
Regulatory CD4 t cells
- function
- structure
- how?
- suppress response of self-reactive CD4 T cells to their specific self antigens
- have T-cell receptors specific for self antigens and are distinguished from other CD4 T cells by the expression of CD25 on the cell surface
- use repressor protein called FoxP3
cytotoxic CD8 T cells
-function
- kill cells that are overwhelmed by intracellular infection
- synthesize cytotoxins in inactive forms and package them into membrane-bound lytic granules
- granule membrane fuses with the plasma membrane of the T cell and discharges its contents onto the target cell surface. In this way, cytotoxic granules neither attack healthy neighbors of an infected cell nor kill the T cell itself
- one cytotoxic T cell can kill many infected cells in succession
- secrete IFN-γ, which inhibits the replication of viruses in infected cells and increases the processing of viral antigens and their presentation by MHC class I molecules
- cytotoxic CD8 T cells kill infected cells through apoptosis which prevents not only pathogen replication but also the release of infectious bacteria or virus particles from the infected cell.
