Naive T cell
In today's world, Naive T cell is a topic that has gained great relevance in all areas of society. From politics to technology, culture and economics, Naive T cell has significantly impacted the way we live and relate. Over the years, Naive T cell has sparked passionate debates and brought about profound changes in the way we approach different aspects of our daily lives. In this article, we will explore the different facets of Naive T cell and analyze its influence in different areas, in order to better understand its impact on today's society.
In immunology, a naive T cell (Th0 cell) is a T cell that has differentiated in the thymus, and successfully undergone the positive and negative processes of central selection in the thymus. Among these are the naive forms of helper T cells (CD4+) and cytotoxic T cells (CD8+). Any naive T cell is considered immature and, unlike activated or memory T cells, has not encountered its cognate antigen within the periphery. After this encounter, the naive T cell is considered a mature 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). It is important to appreciate these differences when assessing naive T cells. Majority of human naive T cells are produced very early in life when infant's thymus is large and functional. 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. The homeostatic proliferation causes change to naive T cell gene expression and i.e. is manifested by acquisition of CD25 surface protein expression.
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
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.
See also
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. S2CID 25144260.
- ^ a b c van den Broek, Theo; Borghans, José A. M.; van Wijk, Femke (2018-03-08). "The full spectrum of human naive T cells". Nature Reviews. Immunology. 18 (6): 363–373. doi:10.1038/s41577-018-0001-y. ISSN 1474-1741. PMID 29520044. S2CID 256745422.
- ^ Rathmell, Jeffrey C.; Farkash, Evan A.; Gao, Wei; Thompson, Craig B. (15 December 2001). "IL-7 Enhances the Survival and Maintains the Size of Naive T Cells". The Journal of Immunology. 167 (12): 6869–6876. doi:10.4049/jimmunol.167.12.6869. PMID 11739504.
- ^ Gattinoni, Luca; Lugli, Enrico; Ji, Yun; Pos, Zoltan; Paulos, Chrystal M.; Quigley, Máire F.; Almeida, Jorge R.; Gostick, Emma; Yu, Zhiya (2011-09-18). "A human memory T cell subset with stem cell-like properties". Nature Medicine. 17 (10): 1290–1297. doi:10.1038/nm.2446. ISSN 1546-170X. PMC 3192229. PMID 21926977.
- ^ Pulko, Vesna; Davies, John S.; Martinez, Carmine; Lanteri, Marion C.; Busch, Michael P.; Diamond, Michael S.; Knox, Kenneth; Bush, Erin C.; Sims, Peter A. (August 2016). "Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses". Nature Immunology. 17 (8): 966–975. doi:10.1038/ni.3483. ISSN 1529-2916. PMC 4955715. PMID 27270402.
- ^ White, Jason T.; Cross, Eric W.; Kedl, Ross M. (June 2017). "Antigen-inexperienced memory CD8+T cells: where they come from and why we need them". Nature Reviews. Immunology. 17 (6): 391–400. doi:10.1038/nri.2017.34. ISSN 1474-1741. PMC 5569888. PMID 28480897.
- ^ a b c d 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. S2CID 6119729. Archived from the original (PDF) on 2014-09-12. Retrieved 2010-12-26.
- ^ Rudd CE, Trevillyan JM, Dasgupta JD, Wong LL, Schlossman S (September 2010). "Pillars article: the CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes". J. Immunol. 185 (5): 2645–9. PMC 3791413. PMID 20724730.
