Naive T cell

In immunology, a naive T cell (T_h0 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.^[1]^[2] 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. ^[3] 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.^[2] For instance, some non-naive T cells express surface markers similar to naive T cells (Tscm, stem cell memory T cells;^[4] Tmp, memory T cells with a naive phenotype^[5]), some antigen-naive T cells have lost their naive phenotype,^[6] 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).^[2] 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⁺, CD62L^low, 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:^[7]

the tyrosine kinase Lck which is associated with co-receptors CD4 and CD8:^[8] 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.^[7] 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.^[7]

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.^[7]

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.