Naive T cell
A naïve T cell (Th0 cell) is a T cell that has differentiated in bone marrow, and successfully undergone the positive and negative processes of central selection in the thymus. Among these are the naïve forms of helper T cells (CD4+) and cytotoxic T cells (CD8+). A naïve T cell is considered mature and, unlike activated or memory T cells, has not encountered its cognate antigen within the periphery.
Naïve T cells are commonly characterized by the surface expression of L-selectin (CD62L); the absence of the activation markers CD25, CD44 or CD69; and the absence of memory CD45RO isoform. They also express functional IL-7 receptors, consisting of subunits IL-7 receptor-α, CD127, and common-γ chain, CD132. In the naïve state, T cells are thought to be quiescent and non-dividing, requiring the common-gamma chain cytokines IL-7 and IL-15 for homeostatic survival mechanisms.
Naïve T cells can respond to novel pathogens that the immune system has not yet encountered. Recognition by a naïve T cell clone of its cognate antigen results in the initiation of an immune response. In turn, this results in the T cell acquiring an activated phenotype seen by the up-regulation of surface markers CD25+, CD44+, CD62Llow, CD69+ and may further differentiate into a memory T cell.
Having adequate numbers of naïve T cells is essential for the immune system to continuously respond to unfamiliar pathogens.
Mechanism of activation
When a recognized antigen binds to the T cell antigen receptor (TCR) located in the cell membrane of Th0 cells, these cells are activated through the following "classical" signal transduction cascade:
- the tyrosine kinase Lck is activated, which results in phosphorylation of
- the CD3 coreceptor complex and ζ-chains of the TCR and activation of the ζ-chain- associated protein Zap70
- activated Zap70 in turn phosphorylates the membrane adaptor Lat, which subsequently recruits several Src homology domain–containing proteins, including phospholipase C-γ1 (PLC-γ1)
- activation of PLC-γ1 results in the hydrolysis of phosphatidylinositol 4,5-bisphosphate to inositol 3,4,5-triphosphate and diacylglycerol
- inositol 3,4,5-triphosphate triggers release of Ca2+ from intracellular stores and diacylglycerol activates protein kinase C and RasGRP
- RasGRP in turn activates the mitogen-activated protein kinase cascade which
An alternative "non-classical" pathway involves activated Zap70 directly phosphorylating the p38 MAPK that in turn induces the expression of the vitamin D receptor (VDR). Furthermore, the expression of PLC-γ1 is dependent on VDR activated by calcitriol. Naïve T cells have very low expression of VDR and PLC-γ1. However activated TCR signaling through p38 upregulates VDR expression and calcitriol activated VDR in turn upregulates PLC-γ1 expression. Hence the activation of naïve T cells is crucially dependent on adequate calcitriol levels.
In summary, activation of T cells first requires activation through the non-classical pathway to increase expression of VDR and PLC-γ1 before activation through the classical pathway can proceed. This provides a delayed response mechanism where the innate immune system is allowed time (~48 hrs) to clear an infection before the inflammatory T cell mediated adaptive immune response kicks in.
Notes and references
- De Rosa SC, Herzenberg LA, Herzenberg LA, Roederer M (February 2001). "11-color, 13-parameter flow cytometry: identification of human naive T cells by phenotype, function, and T-cell receptor diversity". Nat. Med. 7 (2): 245–8. doi:10.1038/84701. PMID 11175858.
- von Essen MR, Kongsbak M, Schjerling P, Olgaard K, Odum N, Geisler C (April 2010). "Vitamin D controls T cell antigen receptor signaling and activation of human T cells" (PDF). Nat. Immunol. 11 (4): 344–9. doi:10.1038/ni.1851. PMID 20208539.