**4.5 Molecular mechanisms of T cell activation**

During T cell activation, membrane-bound inositol phospholipid is hydrolyzed into diacylglycerol (DAG) and IP3. This increases the concentration of cytoplasmic calcium. The elevation in calcium promotes the formation of calcium-calmodulin complexes that activate a number of kinases as well as protein phosphatase IIB or calcineurin. Calcineurin dephosphorylates cytoplasmic nuclear factor of activated T cells (NFAT), permitting its translocation to the nucleus, where it binds to the IL-2 promoter sequence and stimulates transcription of IL-2 mRNA. Numerous other intracellular events, including protein kinase C (PKC) activation by DAG and the activation of nuclear factor kappa B (NF-κB) also occur at the molecular level[10].

#### *Effector stage*

Alloantigen-dependent and -independent factors contribute to the effector mechanisms. Initially, nonimmunologic "injury responses" (ischemia) induce a nonspecific inflammatory response. Because of this, antigen presentation to T cells is increased because of the upregulated expression of adhesion molecules, MHC class II, chemokines, and cytokines. It also promotes the shedding of intact, soluble MHC molecules that may activate the indirect allorecognition pathway. After activation, CD4 T cells initiate macrophage-mediated delayed type hypersensitivity (DTH) responses and provide help to B cells to initiate antibody production.

Various T cells and T cell-derived cytokines such as IL-2 and IFN-γ are upregulated early after transplantation. Later, ß-chemokines, including regulated upon activation, normal T cell expressed and secreted (RANTES), IP-10, and MCP-1 are expressed, promoting intense macrophage infiltration of the allograft. IL-6, TNF-α, inducible nitric oxide synthase (iNOS) and growth factors also play a role in this process. Growth factors, including TGF-ß and endothelin, cause smooth muscle proliferation, intimal thickening, interstitial fibrosis, and, in the case of the kidney, glomerulosclerosis.

Endothelial cells activated by T cell–derived cytokines and macrophages express MHC class II, adhesion molecules, and costimulatory molecules. Therefore, these cells can present antigen and recruit more T cells, amplifying the rejection process. CD8 T cells mediate cellmediated cytotoxicity reactions by inducing cell lysis or apoptosis.
