Naive T cell

Phenotype

Naive T cells are commonly characterized by the surface expression of L-selectin (CD62L) and C-C Chemokine receptor type 7 (CCR7); 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 naive state, T cells are thought to require the common-gamma chain cytokines IL-7 and IL-15 for homeostatic survival mechanisms. While naive T cells are regularly regarded as a developmentally synchronized and fairly homogeneous and quiescent cell population, only differing in T cell receptor specificity, there is increasing evidence that naive T cells are actually heterogeneous in phenotype, function, dynamics and differentiation status, resulting in a whole spectrum of naive cells with different properties. For instance, some non-naive T cells express surface markers similar to naive T cells (Tscm, stem cell memory T cells; Tmp, memory T cells with a naive phenotype), some antigen-naive T cells have lost their naive phenotype, and some T cells are incorporated within the naive T cell phenotype but are a different T cell subset (Treg, regulatory T cells; RTE, Recent Thymic emigrant). The majority of human naive T cells are produced very early in life when the thymus is large and functional. The subsequent decrease in naive T cell production due to involution of the thymus with age is compensated by so called "peripheral proliferation" or "homeostatic proliferation" of naive T cells which have emigrated from the thymus earlier in life. Homeostatic proliferation causes change to naive T cell gene expression and is manifested by surface expression of CD25.

Function

Naive T cells can respond to novel pathogens that the immune system has not yet encountered. Recognition by a naive 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 naive T cells is essential for the immune system to continuously respond to unfamiliar pathogens.

Mechanism of activation

Main article: T cell 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 which is associated with co-receptors CD4 and CD8: is engaged to phosphorylate the CD3 coreceptor complex and ζ-chains of the TCR and to recruit and activate 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. Naive 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 naive 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.

References

1. (February 2001). "11-color, 13-parameter flow cytometry: identification of human naive T cells by phenotype, function, and T-cell receptor diversity". Nat. Med..
2. (2018-03-08). "The full spectrum of human naive T cells". Nature Reviews. Immunology.
3. (15 December 2001). "IL-7 Enhances the Survival and Maintains the Size of Naive T Cells". The Journal of Immunology.
4. (2011-09-18). "A human memory T cell subset with stem cell-like properties". Nature Medicine.
5. (August 2016). "Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses". Nature Immunology.
6. (June 2017). "Antigen-inexperienced memory CD8+T cells: where they come from and why we need them". Nature Reviews. Immunology.
7. (April 2010). "Vitamin D controls T cell antigen receptor signaling and activation of human T cells". Nat. Immunol..
8. (September 2010). "Pillars article: the CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes". J. Immunol..