naive T cell
{{short description|T cell which has not yet encountered its cognate antigen}}
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+). Naive T cells, unlike activated or memory T cells, have 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.{{cite journal |vauthors=De Rosa SC, Herzenberg LA, Herzenberg LA, Roederer M | title = 11-color, 13-parameter flow cytometry: identification of human naive T cells by phenotype, function, and T-cell receptor diversity | journal = Nat. Med. | volume = 7 | issue = 2 | pages = 245–8 |date=February 2001 | pmid = 11175858 | doi = 10.1038/84701 | s2cid = 25144260 }}{{Cite journal|last1=van den Broek|first1=Theo|last2=Borghans|first2=José A. M.|last3=van Wijk|first3=Femke|date=2018-03-08|title=The full spectrum of human naive T cells|journal=Nature Reviews. Immunology|volume=18 |issue=6 |pages=363–373 |doi=10.1038/s41577-018-0001-y|issn=1474-1741|pmid=29520044|s2cid=256745422 }} 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. {{cite journal |author1-link=Jeffrey Rathmell |last1=Rathmell |first1=Jeffrey C. |last2=Farkash |first2=Evan A. |last3=Gao |first3=Wei |last4=Thompson |first4=Craig B. |title=IL-7 Enhances the Survival and Maintains the Size of Naive T Cells |journal=The Journal of Immunology |date=15 December 2001 |volume=167 |issue=12 |pages=6869–6876 |doi=10.4049/jimmunol.167.12.6869 |pmid=11739504 |doi-access=free }} 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;{{Cite journal|last1=Gattinoni|first1=Luca|last2=Lugli|first2=Enrico|last3=Ji|first3=Yun|last4=Pos|first4=Zoltan|last5=Paulos|first5=Chrystal M.|last6=Quigley|first6=Máire F.|last7=Almeida|first7=Jorge R.|last8=Gostick|first8=Emma|last9=Yu|first9=Zhiya|date=2011-09-18|title=A human memory T cell subset with stem cell-like properties|journal=Nature Medicine|volume=17|issue=10|pages=1290–1297|doi=10.1038/nm.2446|issn=1546-170X|pmc=3192229|pmid=21926977}} Tmp, memory T cells with a naive phenotype{{Cite journal|last1=Pulko|first1=Vesna|last2=Davies|first2=John S.|last3=Martinez|first3=Carmine|last4=Lanteri|first4=Marion C.|last5=Busch|first5=Michael P.|last6=Diamond|first6=Michael S.|last7=Knox|first7=Kenneth|last8=Bush|first8=Erin C.|last9=Sims|first9=Peter A.|date=August 2016|title=Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses|journal=Nature Immunology|volume=17|issue=8|pages=966–975|doi=10.1038/ni.3483|issn=1529-2916|pmc=4955715|pmid=27270402}}), some antigen-naive T cells have lost their naive phenotype,{{Cite journal|last1=White|first1=Jason T.|last2=Cross|first2=Eric W.|last3=Kedl|first3=Ross M.|date=June 2017|title=Antigen-inexperienced memory CD8+T cells: where they come from and why we need them|journal=Nature Reviews. Immunology|volume=17|issue=6|pages=391–400|doi=10.1038/nri.2017.34|issn=1474-1741|pmc=5569888|pmid=28480897}} 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|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:{{cite journal | vauthors = von Essen MR, Kongsbak M, Schjerling P, Olgaard K, Odum N, Geisler C | title = Vitamin D controls T cell antigen receptor signaling and activation of human T cells | journal = Nat. Immunol. | volume = 11 | issue = 4 | pages = 344–9 | date = April 2010 | pmid = 20208539 | doi = 10.1038/ni.1851 | s2cid = 6119729 | url = http://www.microbio.uab.edu/CMIJournalClub/March17.pdf | access-date = 2010-12-26 | archive-url = https://web.archive.org/web/20140912193535/http://www.microbio.uab.edu/CMIJournalClub/March17.pdf | archive-date = 2014-09-12 | url-status = dead }}
- the tyrosine kinase Lck which is associated with co-receptors CD4 and CD8:{{cite journal |vauthors=Rudd CE, Trevillyan JM, Dasgupta JD, Wong LL, Schlossman S | title =Pillars article: the CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes | journal = J. Immunol. | volume = 185 | issue = 5 | pages = 2645–9 |date=September 2010 | pmid = 20724730 | pmc=3791413}} 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.