From the hematopoietic stem cells lymphoid progenitor cells form in the bone marrow. Upon exiting this they proceed to the thymus to mature and undergo positive and negative selection. T precursor cells enter the Thymus into the subcapsular cortical areas and proliferate. They move from here towards the medulla.
Step 1 is to be a double negative cell (DN), meaning they do not yet express CD4 or CD8, but they do express CD2. CD2 is a membrane protein found on T and NK cells. CD2 is a receptor for CD58. The beta chain of the TCR undergoes V-D-J rearrangement and then is presented on the Tcell membrane with CD3 and a surrogate alpha chain. Signaling through this preT receptor triggers a stop to beta chain rearrangement and induces proliferation. At this point CD4 and CD8 are expressed and the T cells are double positive (DP). Rag1/2 is expressed and the alpha chain undergoes V-J rearrangement. These cells then go to the cortico-medullary junction for positive and negative selection.
Positive selection is when double positive cells bind cortical epithelial cells with high enough affinity to obtain a survival signal. After this point the cell must choose to become a cytotoxic T cell or a CD4+ T cell and migration further into the cortico-medullary junction. Negative selection then occurs inducing apoptosis in cells with high enough binding affinity. These selection occurs on self peptides loaded into MHC molecules. Those cells surviving both selection processes and presenting only CD4 or CD8 on their surface are released into the periphery. “These cells are self-restricted, self-tolerant, and singly positive” – wiki
Development in the thymus is the time when ‘self’ is defined for the organism. The selection of T cells created in the thymus will proceed for the duration of the organisms life. The thymus is the largest at birth and then begins to decline.
Types of T Cells
These cytotoxic T cells response to peptides presented in MHCI molecules which are present on all nucleated cells (not erythroblasts: red blood cells). The CD8 molecule interacts with the MHCI molecule.
These are considered helper T cells that assist in the maturation of B cells and activation of cytotoxic T cells and macrophages. Their major mechanism of doing so is through the secretion of cytokines. These cells express CD4 on their membrane which interacts along side the TCR on MHCII molecules on antigen presenting cells. CD4 recruits Lck (kinase) with its intracellular domain.
There are subset of these cells, each with a different function and develop depending on the cytokine environment of the cell. Activated CD4+ cells secrete IL-2, IL-4, and IFN-gamma.
- These cells are effective against intracellular bacteria and protozoa.
- These cells are induced by IL-12 and IL-2 and inhibited by IL-10 and IL-4. They effect macrophages, CD8+ T cells, IgG B cells, and IFN-gamma CD4+ T cells. Their transcription factors are STAT4 and T-bet. They secrete IFN-gamma which can activate macrophages, and IL-2.
- These cells are effective against extracellular parasites.
- These cells are induced by IL-4 and inhibited by IFN-gamma. These cells secrete IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13. They effect eosinophils, basophils, mast cells, B cells, and IL-4/IL-5 CD4 T cells. Their transcription factors are STAT6 and GATAs.
- These cells are effective against extracellular bacteria and fungi. The are associated with auto immune diseases.
- These cells are induced by IL-6, TGFbeta, and IL-23. It secretes IL-17, IL-21, and IL-22. They effect neutrophils and IgM/IgA B cells and IL-17 CD4 cells. Their transcription factors are STAT3 and RORg.
- These play a role in immunological tolerance. They are responsible for limited the immune response and down regulating the T cell response and are selected during negative selection as those cells binding too strongly. These cells can be identified by extracellular marker: FoxP3+
- These cells are found in the periphery of B cell follicles of secondary lymph tissues. They express B cell follicle homing receptor CXCR5. They are important in maintenance of germinal centers. They are important in establishing tolerance of B cells to self.
- These cells secrete IL-21 and IL-4.
These are T cells with a gamma and delta chain rather than an alpha and beta chain.
Natural Killer-like T Cells
These cells bridge the adaptive and the innate immune system. These recognize peptides presented by CD1.
These are T cells that retain the antigen affinity of the activated T cell. These are used during a second immune response to decrease response time.
These cells are activated by engaging their TCR and a co-stimulatory molecule. Without the secondary signal the cell assumes it is autoreactive and will proceed into a state of anergy. Naive T cells only express CD28 as a secondary signaling molecule and it is only with activation that OX40, ICOS, and others are expressed.
The TCR is composed of many elements. The T cell receptor is composed of the CD3 proteins (CD3gamma-epsilon & CD3gamma-delta and CD3zeta homodimer), TCRalpha, and TCRbeta.
Under activation the T cell receptor (TCR) binds to the MHC complex on the target cell (signal 1) and receives a co-stimulatory signal from CD28 interacting with CD80/86 on the target cell (signal 2). LFA-1 on the T cell and ICAM on the target cell are responsible for cell adhesion.
- TCR binds MHC molecule on target cell. CD4 or CD8 also binds MHC.
- Lck is activated on CD4 or CD8 and phosphorylates the intracellular ITAM motifs on the CD3 molecules. 10 ITAMs: 1 each on CD3 gamma, delta, and eplison. 3 each on zeta chains.
- Phosphorylated ITAMs recruit Zap-70 (kinase). Zap-70 binds to ITAMs and becomes phosphorylated and activated by Lck. It can also autophosphorylate.
- Zap-70 then can phosphorylate LAT and SLP-76. LAT and SLP-76 are linked by Gads.
- PIP2 is converted in the plasma membrane to PIP3 by PI3K. PLC-gamma binds to PIP3 with the help of a co-stimulatory signal from membrane bound CD28. CD28 is responsible for activation of PI3K. At this time Lck recruits and phosphorylates Itk, a membrane associated tyrosine kinase.
- PLC-gamma is phosphorylated by Itk and it then binds to phosphorylated LAT and SLP-76. PLC-gamma is the gate keeper of T cell activation.
- PLCgamma cleaves PIP2 into DAG, membrane bound, and IP3, diffuses into cytosol.
- This marks the branch point of T cell activation.
- IP3 diffuses to the ER and triggers Ca2+ channels to open, releasing Ca2+ into the cytosol. This activates NFAT transcription factors, which are phosphorylated in the cytosol, preventing their translocation to the nucleus. Ca2+ binds to calmodulin in the cytosol causing it to undergo a conformational change meaning it can now bind calcineurin, a protein phosphatase that acts on NFAT. Calcineurin removes NFAT’s phosphate allowing it to enter the nucleus where it is a TF for IL-2 and PD-1.
- DAG recruits Ras-GRP and PKCtheta (protein kinase theta) to the plasma membrane.
- Ras-GRP is a GEF for Ras, which activates it. LAT/SLP-76 also recruits GRB2 and SoS which is a GEF for Ras. Ras activates the MAPK cascade, possible because of the scaffolding protein KSR1. Activated ERK1/2 phosphorylates Elk-1 which serves as a TF for Fos, one of the components of AP-1 (heterodimer of Fos and Jun TFs). JNK, a MAPK product, enters the nucleus and phosphorylates c-Jun which activates the Jun-Fos dimer for transcription.
- Recruitment of PKC-theta (present mostly in muscle and T cells) activates CARMA1 which oligomerizers into a multiunit complex. This complex serves as a scaffold for BCL10 and MALT1. This complex recruits TRAF6, which which creates a poly-ubiquitin saffold on itself and NEMO. (gamma of the IKK g protein complex). TAK1 is trecruited by TAB1.2 to phorphorylate IKKbeta which phosproylates IkB a subunit attached to NFKB. THis leads to degradation of IkB, releasing NFkB allowing NFkB be activated, move to the nucleus and act as a transcription factor.
Co-stimulatory molecules are required for signal transduction in T cells. Specifically CD28 binds to CD80/86, members of the B7 protein family which are expressed on the surface of mostly APC. This is another checkpoint mechanism to ensure that T cells are only activated in response to infection not by bystander cells presenting antigen on their surface.
Engagement of CD28 by CD80/86 causes phosphorylation on its tyrosine residues by Lck. This phosphorylation serves to activate PI3K to generate PIP3.
MHCI 8-9 aa peptides
MHCII 12-25 aa peptides
- Allergy. IgE ab. Th2 response.
- ADCC. Ab tag self cells. Auto immune Th2
- Non clearance of ag-ab complexes.
- Cell mediated. Rheumatoid arthritis, Multiple sclerosis.