Naive T cell
Encyclopedia
A naive T cell or Th0 cell is a T cell
that has differentiated in bone marrow
, and successfully undergone the positive and negative processes of central selection
in the thymus
. A naive T cell is considered mature and unlike activated T cells or memory T cells
it has not encountered its cognate antigen
within the periphery.
(CD62L); the absence of the activation markers CD25
, CD44
or CD69
; and the absence of memory CD45RO
isoform. They also express functional IL-7 receptor, consisting of subunits IL-7 receptor-α, CD127, and common-γ chain, CD132. In the naive state, T cells are thought to be quiescent and non-dividing, requiring the common-gamma chain cytokines IL-7
and IL-15
for homeostatic survival.
s 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.
(TCR) located in the cell membrane of Th0 cells, these cells are activated through the following "classical" signal transduction
cascade:
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.
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
that has differentiated in bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
, and successfully undergone the positive and negative processes of central selection
Central tolerance
Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self. The concept of central tolerance was proposed in 1959 by Joshua Lederberg, as part of his general theory of immunity and tolerance, and is often mistakenly attributed to MacFarlane...
in the thymus
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
. A naive T cell is considered mature and unlike activated T cells or memory T cells
Memory T cells
Memory T cells are a subset of infection- as well as potentially cancer-fighting T cells that have previously encountered and responded to their cognate antigen; thus, the term antigen-experienced T cell is often applied. Such T cells can recognize foreign invaders, such as bacteria or viruses,...
it has not encountered its cognate antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
within the periphery.
Phenotype
Naive T cells are commonly characterized by the surface expression of L-selectinL-selectin
L-selectin, also known as CD62L, is a cell adhesion molecule found on leukocytes. It belongs to the selectin family of proteins, which recognize sialylated carbohydrate groups...
(CD62L); the absence of the activation markers CD25
CD25
CD25 is the alpha chain of the IL-2 receptor. It is a type I transmembrane protein present on activated T cells, activated B cells, some thymocytes, myeloid precursors, and oligodendrocytes that associates with CD122 to form a heterodimer that can act as a high-affinity receptor for IL-2.CD25 is...
, CD44
CD44
The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the CD44 gene.- Tissue distribution and isoforms :...
or CD69
CD69
CD69 is a human transmembrane C-Type lectin protein encoded by the gene.-Further reading:...
; and the absence of memory CD45RO
CD45
Protein tyrosine phosphatase, receptor type, C also known as PTPRC is an enzyme that, in humans, is encoded by the PTPRC gene. PTPRC is also known as CD45 antigen , which was originally called leukocyte common antigen.- Function :The protein encoded by this gene is a member of the protein tyrosine...
isoform. They also express functional IL-7 receptor, consisting of subunits IL-7 receptor-α, CD127, and common-γ chain, CD132. In the naive state, T cells are thought to be quiescent and non-dividing, requiring the common-gamma chain cytokines IL-7
Interleukin 7
IL-7 a hematopoietic growth factor secreted by stromal cells in the red marrow and thymus. It is also produced by keratinocytes, dendritic cells, hepatocytes, neurons, and epithelial cells but is not produced by lymphocytes.- Genetics :...
and IL-15
Interleukin 15
Interleukin 15 is a cytokine with structural similarity to IL-2. Like IL-2, IL-15 binds to and signals through the IL-2/IL-15 beta chain and the common gamma chain . IL-15 is secreted by mononuclear phagocytes following infection by virus...
for homeostatic survival.
Function
Naive T cells can respond to novel pathogenPathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
s 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
Adaptive immune system
The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic growth. Thought to have arisen in the first jawed vertebrates, the adaptive or "specific" immune system is activated by the “non-specific” and evolutionarily older innate...
. 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 receptorT cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
(TCR) located in the cell membrane of Th0 cells, these cells are activated through the following "classical" signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
cascade:
- the tyrosine kinase LckLckLck is a protein that is found inside specialized cells of the immune system called lymphocytes. Lck is a tyrosine kinase, which phosphorylates tyrosine residues of certain proteins involved in the intracellular signaling pathways of these lymphocytes...
is activated, which results in phosphorylationPhosphorylationPhosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of - the CD3 coreceptor complex and ζ-chains of the TCR and activation of the ζ-chain- associated protein Zap70
- activated Zap70 in turn phosphorylates the membrane adaptor Lat, which subsequently recruits several Src homology domainSrc homology domainIn biology, a Src homology domain is one of the two small protein binding domains found in the Src oncoprotein. Homologs of both the Src homology 2 and Src homology 3 domains are found in numerous other proteins....
–containing proteins, including phospholipase C-γ1PLCG1Phospholipase C, gamma 1, also known as PLCG1, is a protein that in humans is encoded by the PLCG1 gene.-Function:The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate...
(PLC-γ1) - activation of PLC-γ1 results in the hydrolysis of phosphatidylinositol 4,5-bisphosphatePhosphatidylinositol 4,5-bisphosphatePhosphatidylinositol 4,5-bisphosphate or PtdInsP2, also known simply as PIP2, is a minor phospholipid component of cell membranes...
to inositol 3,4,5-triphosphate and diacylglycerol - inositol 3,4,5-triphosphate triggers release of Ca2+Calcium in biologyCalcium plays a pivotal role in the physiology and biochemistry of organisms and the cell. It plays an important role in signal transduction pathways, where it acts as a second messenger, in neurotransmitter release from neurons, contraction of all muscle cell types, and fertilization...
from intracellular stores and diacylglycerol activates protein kinase CProtein kinase CProtein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
and RasGRPRASGRP1RAS guanyl-releasing protein 1 is a protein that in humans is encoded by the RASGRP1 gene.- Function :RAS guanyl nucleotide-releasing protein is a member of a family of genes characterized by the presence of a Ras superfamily guanine nucleotide exchange factor domain... - RasGRP in turn activates the mitogen-activated protein kinaseMitogen-activated protein kinaseMitogen-activated protein kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.-Activation:MAP kinases are activated...
cascade which ultimately upregulates gene expression and causes entry into the cell cycleCell cycleThe cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
An alternative "non-classical" pathway involves activated Zap70 directly phosphorylating the p38
P38 mitogen-activated protein kinases
P38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation and apoptosis....
MAPK that in turn induces the expression of the vitamin D receptor
Calcitriol receptor
The calcitriol receptor, also known as the vitamin D receptor and also known as NR1I1 , is a member of the nuclear receptor family of transcription factors...
(VDR). Furthermore, the expression of PLC-γ1 is dependent on VDR activated by calcitriol
Calcitriol
Calcitriol , also called 1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D3, is the hormonally active form of vitamin D with three hydroxyl groups...
. 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
Innate immune system
The innate immune system, also known as non-specific immune system and secondary line of defence, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner...
is allowed time (~48 hrs) to clear an infection before the inflammatory T cell mediated adaptive immune response
Adaptive immune system
The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic growth. Thought to have arisen in the first jawed vertebrates, the adaptive or "specific" immune system is activated by the “non-specific” and evolutionarily older innate...
kicks in.