# Naive T cell

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In [immunology](/source/Immunology), a **naive T cell** (**Th0 cell**) is a [T cell](/source/T_cell) that has [differentiated](/source/Cellular_differentiation) in the [thymus](/source/Thymus), and successfully undergone the positive and negative processes of [central selection](/source/Central_tolerance) in the thymus. Among these are the naive forms of [helper T cells](/source/Helper_T_cells) ([CD4](/source/CD4)+) and [cytotoxic T cells](/source/Cytotoxic_T_cells) ([CD8](/source/CD8)+). Naive T cells, unlike activated or [memory T cells](/source/Memory_T_cells), have not encountered its cognate [antigen](/source/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](/source/L-selectin) (CD62L) and [C-C Chemokine receptor type 7](/source/C-C_chemokine_receptor_type_7) (CCR7); the absence of the activation markers [CD25](/source/CD25), [CD44](/source/CD44) or [CD69](/source/CD69); and the absence of memory [CD45RO](/source/CD45) isoform.[1][2] They also express functional [IL-7 receptors](/source/Interleukin-7_receptor), consisting of subunits IL-7 receptor-α, [CD127](/source/CD127), and common-γ chain, [CD132](/source/CD132). In the naive state, T cells are thought to require the common-gamma chain cytokines [IL-7](/source/Interleukin_7) and [IL-15](/source/Interleukin_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](/source/Regulatory_T_cell), regulatory T cells; RTE, Recent Thymic emigrant).[2] 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](/source/Pathogen) 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](/source/Adaptive_immune_system). 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](/source/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](/source/T_cell_activation)

When a recognized antigen binds to the [T cell antigen receptor](/source/T_cell_receptor) (TCR) located in the cell membrane of Th0 cells, these cells are activated through the following "classical" [signal transduction](/source/Signal_transduction) cascade:[7]

- the tyrosine kinase [Lck](/source/Lck) which is associated with co-receptors CD4 and CD8:[8] is engaged to phosphorylate the [CD3](/source/CD3_(immunology)) coreceptor complex and ζ-chains of the TCR and to recruit and activate the ζ-chain- associated protein [Zap70](/source/Zap70)
- activated Zap70 in turn phosphorylates the membrane adaptor [Lat](/source/Linker_for_Activation_of_T_cells), which subsequently recruits several [Src homology domain](/source/Src_homology_domain)–containing proteins, including [phospholipase C-γ1](/source/PLCG1) (PLC-γ1)
- activation of PLC-γ1 results in the hydrolysis of [phosphatidylinositol 4,5-bisphosphate](/source/Phosphatidylinositol_4,5-bisphosphate) to [inositol 3,4,5-triphosphate](/source/Inositol_trisphosphate) and [diacylglycerol](/source/Diacylglycerol)
- inositol 3,4,5-triphosphate triggers release of [Ca2+](/source/Calcium_in_biology) from intracellular stores and diacylglycerol activates [protein kinase C](/source/Protein_kinase_C) and [RasGRP](/source/RASGRP1)
- RasGRP in turn activates the [mitogen-activated protein kinase](/source/Mitogen-activated_protein_kinase) cascade which

An alternative "non-classical" pathway involves activated Zap70 directly phosphorylating the [p38](/source/P38_mitogen-activated_protein_kinases) MAPK that in turn induces the expression of the [vitamin D receptor](/source/Calcitriol_receptor) (VDR). Furthermore, the expression of PLC-γ1 is dependent on VDR activated by [calcitriol](/source/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](/source/Innate_immune_system) is allowed time (~48 hrs) to clear an infection before the inflammatory T cell mediated [adaptive immune response](/source/Adaptive_immune_system) kicks in.[7]

## See also

- [Immune system](/source/Immune_system)
- [Memory T cells](/source/Memory_T_cells)

## Notes and references

1. 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](https://doi.org/10.1038/84701). [PMID 11175858](https://pubmed.ncbi.nlm.nih.gov/11175858). [S2CID 25144260](https://api.semanticscholar.org/CorpusID:25144260)

1. 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](https://doi.org/10.1038/s41577-018-0001-y). [ISSN 1474-1741](https://www.worldcat.org/issn/1474-1741). [PMID 29520044](https://pubmed.ncbi.nlm.nih.gov/29520044). [S2CID 256745422](https://api.semanticscholar.org/CorpusID:256745422)

1. 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](https://doi.org/10.4049/jimmunol.167.12.6869). [PMID 11739504](https://pubmed.ncbi.nlm.nih.gov/11739504)

1. 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](https://doi.org/10.1038/nm.2446). [ISSN 1546-170X](https://www.worldcat.org/issn/1546-170X). [PMC 3192229](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3192229). [PMID 21926977](https://pubmed.ncbi.nlm.nih.gov/21926977)

1. 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](https://doi.org/10.1038/ni.3483). [ISSN 1529-2916](https://www.worldcat.org/issn/1529-2916). [PMC 4955715](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4955715). [PMID 27270402](https://pubmed.ncbi.nlm.nih.gov/27270402)

1. 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](https://doi.org/10.1038/nri.2017.34). [ISSN 1474-1741](https://www.worldcat.org/issn/1474-1741). [PMC 5569888](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569888). [PMID 28480897](https://pubmed.ncbi.nlm.nih.gov/28480897)

1. 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"](https://web.archive.org/web/20140912193535/http://www.microbio.uab.edu/CMIJournalClub/March17.pdf). *Nat. Immunol.*. **11** (4): 344–9. [doi:10.1038/ni.1851](https://doi.org/10.1038/ni.1851). [PMID 20208539](https://pubmed.ncbi.nlm.nih.gov/20208539). [S2CID 6119729](https://api.semanticscholar.org/CorpusID:6119729). Archived from [the original](http://www.microbio.uab.edu/CMIJournalClub/March17.pdf) on 2014-09-12. Retrieved 2010-12-26.

1. 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](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791413). [PMID 20724730](https://pubmed.ncbi.nlm.nih.gov/20724730)

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Adapted from the Wikipedia article [Naive T cell](https://en.wikipedia.org/wiki/Naive_T_cell) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Naive_T_cell?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.