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Explaining T cell activation and its pathway

Submitted by abnguyen on Thu, 05/04/2017 - 23:46

 

The affinity of T-cell receptors for MHC is usually too low to mediate a functional interaction between the two cells by itself.  In order to increase signal strength and cell to cell interactions, accessory receptors are required.  Unlike T-cell receptors or MHC proteins, accessory receptors do not bind foreign antigens and are invariant.  The accessory receptors that have a direct role in activating T-cells are called co-receptors.  The most understood co-receptors are CD4 and CD8.  Both proteins are single-pass transmembrane protein and recognize MHC, however, unlike T-cell receptors, CD4 and CD8 bind to non variable parts of the protein. The antibodies to CD4 and CD8 are used to help distinguish between the 2 main classes of T cells. (Smith-Garvin et al, 2017)

    Signaling through TCR alone results in a non responsive state (anergy).  Additional binding to other surface receptors are needed to enhance TCR signals.  The most used and robust receptor is the CD28 protein.  A study done on mice with CD28 knocked out showed a plethora of immune defects such as impaired T-cell activation, a lack of T-cell help for B cells and poor memory of T-cell response (Harris NL. and Ronchese F 1999).  CD28 promotes T-cell proliferation, cytokine production, cell survival, and cellular metabolism.  Many of these processes are activated when TCR binding occurs alone but the signal is not sufficient enough to pass a threshold and requires CD28 co-binding. (Alberts et al, 2002).  CD28 is located on T cells and binds with either CD80 (B7-1) or CD86 (B7-2) on APC.  CD80 and CD86 are expression is upregulated in response to inflammatory stimuli thus leading ligand upregulation to be seen as a key link between danger signals and an immune response.

    T cell activation requires multiple steps after the initial bindings of MHC to TCR and CD28 to either CD80 or CD86 as shown in figure 4. (a higher resolution image can be found at http://tinyurl.com/m6fdl99).  The final product of this extensive pathway is the production of IL-2 which leads to an immune response.  To being the process, CD28 and CD45 activates tyrosine kinases Lck and Fyn.  These 2 activations phosphorylate ZAP70, SYK, Vav1 and LAT.  LAT binds to GADS, SLP76, ITK, Vav1 and Tec which leads to the activation of PLC-γ, RLK, CARMA1, BCL10, CDC42 and Rac.  Rac activation is essential for MEKK1, MKKs and JNK activation.  JNKs phosphorylates c-Jun and c-Fos within the nucleus and will allow for IL-2 transcription.  The recruitment of these signal transduction components drive T-cell activation.

    On the left side of the pathway, CD28 binds to PI3K, recruiting it to the membrane.  PI3K activates AKT which promotes T-cell survival.  The PLC-γ protein that was activated earlier uses the PIP2 created from PI3k as a substrate to produce PI3 and DAG.  PI3 releases Ca2+ into the cytoplasm which will send NFAT into the cytoplasm.  While this process is occurring, PKC-ϴ is regulating the phosphorylation of IKK with the aid of CARMA1, BCL10 and MALT1.  IKK phosphorylation will degrade I-κBs, freeing NF-κB allowing it to travel into the nucleus.  

    Once NFAT, NF-κB, c-Jun, and c-Fos are inside of the nucleus, IL-2 will begin to be transcribed.  IL-2 transcription allows the T-cell to enter into the cell cycle, promotes cell survival, cell differentiation, and most importantly, the activation of helper T cells. (Smith-Garvin et al, 2017)

Smith-Garvin, Jennifer E., Gary A. Koretzky, and Martha S. Jordan. “T Cell Activation.” Annual review of immunology 27 (2009): 591–619. PMC. Web. 4 May 2017.

Harris NL. and Ronchese F.  1999 "The role of B7 costimulation in T-cell immunity".  Immunology and Cell Biology.  <http://www.nature.com/icb/journal/v77/n4/full/icb199938a.html>.  Accessed 3 May 2017.

Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. T Cells and MHC Proteins.

http://tinyurl.com/m6fdl99

 

 

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