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T cellComments

T cell

So many names for T cells!

T cells -- also known as T lymphocytes or thymocytes -- do not recognize antigens floating in solution. They only recognize antigens presented by antigen-presenting cells. T cells are broken into two classes: CD8 cells (aka cytotoxic T cells, CTLs or TC cells) which are T cells expressing CD8 cell surface proteins, and respond to Class I MHC; and CD4 cells (aka helper T cells or TH cells) which express CD4 cell surface proteins and respond to Class II MHC.

All T cells contain a T cell receptor (TCR), which is activated only by antigens embedded in an MHC complex.

TCRs and antibodies are similar in that they both specifically bind antigens, but they are critically different because TcRs only bind MHC-associated antigens and an antibody will bind a free (floating) or membrane-bound antigen.

When a TcR is activated by an antigen-MHC complex, its associated T cell will release a plethora of cytokines. Cytokines are used by the immune system to communicate within itself and with other tissues.

CD4 cells (helper T cells) (TH cells)

T cells expressing CD4 surface protein are called helper T cells (aka TH cells) or effector T cells or any variation with the word lymphocyte in place of cell.

CD4 cells play important roles in B cell activation and release lots of cytokines. TH cells begin as TH0 cells, but then differentiate into either TH1, TH2 or TH17 cells. TH1 and TH2 cells cross-regulate each other. However, an individual TH cell only produces one cytokine; thus, TH1 and TH2 effects are on the level of the entire body. CD8 cells do not release as many cytokines, but eliminate virally infected and cancer cells, and are important for autograft rejection. Remember that CTL activity only occurs with TH help.

TH1 CellsTH1 cells are inflammatory cells which secrete: IL-2; IFN-γ, which inhibits TH2 proliferation and interferes with IL-4 effects; and TFN-β, which activates macrophages. In less technical words, TH1 cells activate macrophages and stimulate T cell responses.
TH2 CellsTH2 cells are helper T cells which secrete: IL-4, which interferes with IFN-γ effects; IL-10, which inhibits IFN-γ synthesis; and IL-5, which stimulates B cell and eosinophil growth and differentiation.
TH17 CellsLocated on mucosal surfaces, TH17 cells express CD4+ surface proteins (they are CD4+) and fight bacterial infections. TH17 cells secrete IL-17, an important inflammatory cytokine, and IL-22, a cytokine inducing production of antibacterial defensins. TH17 differentiation (and maintenance) is stimulated by IL-23 and is distinct from TH1 and TH2 cell production; TH17 differentiation is inhibited by IFN-γ and IL-4.
TS CellsSeparate from TH cells are CD4+CD25+ suppressor T (TS) cells. TS cells have a subpopulation of regulatory T (Treg) cells which suppress immune responses. This is critical to prevent autoimmune diseases, and to help control the damaging immune mechanisms (such as inflammation) from overperforming.
T1 vs TH2

Naïve CD4 T cells activated in presence of IL-12 and IFN-γ are committed to TH1 lineage. Naïve CD4 T cells activated in presence of IL-4 (and especially if IL-6 is also present) are committed to TH2 lineage. These cytokines are secreted by the cells which respond appropriately to a given pathogen. TH1 and TH2 cells amplify their own populations. TH1 cells secrete IFN-γ, inhibiting TH2 proliferation. TH2 cells secrete IL-10 and TGF-β, inhibiting activation and growth of TH1 cells.

There are multiple diseases related to TH1 and TH2 cells.

Experimental Allergenic Encephalomyelitis (EAE) is caused by a faulty TH1 response to myelin basic proteins of the central nervous system. Leprosey results from an inappropriate TH2 cell activity and is carried by a dominant allele. Allergies are causes by TH2 responses that lead to preferential IgE production.

Also, as AIDS progresses, TH1 cells become TH2 cells, and TH17 cells rapidly disappear into the gut.

Virgin T cells migrate from the thymus through the blood, eventually flowing into capillaries at a lymph node and then through post-capillary venules (PCVs) into the node itself.

T cells sometimes activate and exit lymph nodes to patrol the bloodstream. These circulating, activated T cells have two fates: extravasation to an infection site (detailed) below, following by reversion to a memory state and flow through the lymph to the nearest lymph node; or, if no extravasation occurs, reversion to a memory state after a few days of circulation, followed by crossing out of blood through PCVs and then flow to the nearest lymph node.

CD8 cells (cytotoxic T cells) (TC cells)

T cells expressing CD8 surface protein are called cytotoxic T cells (aka TC cells, TC cells or any variation with the word 'lymphocyte' in place of 'cell'). Cytotoxic T cells recognize surface markers on other cells in the body that label those cells for destruction. In this way, TCs help to keep virus-infected or malignant cells in check. Also, manipulation of antigen presenting TC cells is important for immune system targeting of tumor cells.

T cell activation

One of the central mechanisms of the immune system is thymocyte activation, clonal expansion and differentiation (into either effector or memory cells). T cells are activated by binding of the TCR-CD3 complex to a processed antigen peptide bound to a Class I (CD8 cells, aka cytotoxic T cells) or a Class II (CD4, aka helper T cells) MHC molecule. A cascade of biochemical events is initiated, inducing the resting thymocyte to proliferate and differentiate. Induction occurs in two steps: initiation and signal generation, described below. This leads to expression of various gene products, listed below by how early they are expressed after initiation.

InitiationThe TCR-CD3 complex binds the peptide-MHC complex, bringing the thymocyte and the antigen-presenting cell together. Next, CD4 or CD8 coreceptors bind invariant regions of the MHC molecule. At this point, the tyrosine kinase p56Lck is brought close to the cytoplasmic tails of the TCR. p56Lck is essential for initiation of TCR signaling, and in a resting thymocyte it is sequestered from the TCR in a lipid raft. Upon binding of the coreceptors to their ligands, however, the lipid raft moves to the TCR so that p56Lck can phosphorylate the ITAMs of the TCR complex. Phosphorylated tyrosines in the ITAMs of the CD3 ζ chain bind and activate ZAP-70 and other molecules, which catalyzes phosphorylation of various membrane-associated adaptor molecules. Phosphorylated membrane-associated adaptor molecules aid recruitment of signal transduction pathway mediators. Initiation triggers a litany of signal transduction pathways, described immediately below.
Transduction
Phospholipase CPhospholipase C (PLCγ) is bound and activated by the phosphorylated CD3 ζ chain, and hydrolizes phosphoinositol biphosphate (PIP2) to form inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 causes a rapid Ca2+ release from the endoplasmic reticulum and opens Ca2+ channels in the cell membrane. DAG activates the multifunctional protein kinase C, which phosphorylates in various pathways. Ca2+ release leads to transport of NFAT (a transcription factor) from the cytoplasm into the nucleus, where it indirectly activates expression of cytokines which promote thymocyte growth.
Protein Kinase CProtein Kinase C (PKC) is activated by DAG (mentioned above) to translocate to lipid rafts and initiate a cascade that leads to activation of the transcription factor NF-κB.
Nuclear Factor κBNuclear Factor Kappa B (NF-κB) is a widespread transcription factor that activates various thymocyte genes, including the very critical IL-2. PKC activation (mentioned above) leads to assembly of a membrane-bound complex that activates inhibitor of κB kinase (IKK); in turn, IKK inactivates inhibitor of κB (IκB) via phosphorylation. This leaves NF-κB free to perform its functions.
Ras/Map KinaseThe Ras/Map Kinase Pathway is conserved amongst eukaryotes. Ras is a small G protein which is activated by GTP to initiate the mitogen activated protein kinase (MAP Kinase) pathway. ERK, The end product of the MAP Kinase pathway, is phosphorylated and activates Elk. Elk is a transcription factor necessary for expression of Fos. Fos is phosphorylated by MAP Kinase and associates with Jun to form AP-1. AP-1 is an essential transcription factor for T cell activation and IL-2 transcription.

Naive thymocytes are those which have not yet encountered a peptide-MHC complex. Arrested in G0, naive thymocytes have condensed chromatin, minimal cytoplasm and little transcriptional activity. They continuously recirculate through blood, lymph an lymph nodes. To activate, they need additional costimulatory signals to those described above. Signal 1 is the initial interaction between TCR-CD3 and peptide-MHC. Signal 2 is is provided by thymocyte CD28 and CD152 interaction with B7 proteins on the antigen-presenting cell. B7 proteins are constitutively expressed on dendritic cells, and in activated macrophages and activated B cells. B7 binds two proteins -- CD28 and CD152 -- which are both found on thymocyte membranes as disulfide-linked dimers. Binding of CD28 induces the cell to activate, while binding of CD152 represses activation. CD152 has a much higher B7 affinity than CD28, and its expression is activated by binding of CD28. Thus, CD152 is essentially a braking mechanism that maintains homeostasis; CD152 knockout mice have enlarged lymph nodes, enlarged spleen and die 3-4 weeks after birth. In the absence of a costimulatory signal, an unresponsive state called clonal anergy ensues (as opposed to clonal proliferation).

Gene GroupOverview
ImmediateImmediate genes are expressed within ½ hour of antigen recognition, and encode mostly transcription factors.
ProductLocationOverview
c-FosNucleusProto-oncogene & nuclear-binding protein.
c-JunNucleusCellular oncogene & transcription factor.
NFATNucleusTranscription factor.
c-MycNucleusCellular oncogene.
NF-κBNucleusTranscription factor.
EarlyEarly genes are expressed within 1-2 hours of antigen recognition. and encode mostly cytokines.
ProductLocationOverview
IFN-γSecretedCytokine
IL-2SecretedCytokine
Isulin ReceptorMembraneHormone receptor.
IL-3SecretedCytokine
TGF-βSecretedCytokine
p55MembraneAka IL-2 Receptor, a cytokine receptor.
TNF-βSecretedCytokine
CyclinCytoplasmCell cycle protein.
IL-4SecretedCytokine
IL-5SecretedCytokine
IL-6SecretedCytokine
c-MybNucleusProto-oncogene.
GM-CSFSecretedCytokine
LateLate genes are expressed more than 2 days after antigen recognition, and encode various adhesion molecules.
ProductLocationOverview
HLA-DRMembraneClass II MHC molecule.
VLA-4MembraneAdhesion molecule.
VLA-1,2,3,5MembraneAdhesion molecules.

In essence, activation occurs when a dendritic cell simultaneously binds itself to a TH's antigen receptor (primary signal) and to its CD28 receptor (secondary signal). This signals to the dendritic cell that the antigen is foreign (dangerous) and that the next encountered cytotoxic thymocyte must be activated. Other times, dendritic cells are directly activated by an antigen via toll-like receptors and activate cytotoxic thymocytes -- this is a critical example of how innate immunity activates adaptive immunity.

Clonal expansion and differentiation

The primary response is activation of naive thymocyte by a peptide-MHC complex. ∼48 hours after activation, the thymocyte enlarges into a blast cell and repeatedly divide to form a population of genetically identical cells (clonal expansion). Remember the G proteins described under transduction, and that G proteins help trigger the G1 phase of the cell cycle). IL-2 concentration increases 100x in activated cells, helping induce up to 2-3 daily divisions for 4-5 days as well as thymocyte differentiation into either effector T cells or memory T cells.

Cell TypeOverview
EffectorDerived from naive cells and memory cells, effector T cells have short lives of only a few days or a few weeks and carry out specialized functions including: cytokine secretion; B-cell help, performed by activated CD4+ cells, aka TH cells; and cytotoxic killing, performed by activated CD8+ cells, aka CTLs. Effector thymocytes and naive thymocytes express different cell membrane molecules, leading to different recirculation cycles.
MemoryDerived from naive cells and effector cells, memory T cells are long-lived, quiescent cells with heightened reactivity to subsequent antigen exposure. Like naive cells, they are arrested in G0; however, they are activated more easily and by more cell types than naive thymocytes. Their cell surface markers are not distinguishable different from effector cells, although their recirculation cycles are different from naive and effector cells.

T Cell Death

Over 98% of all thymocytes die during positive and negative selection, with the remaining cells entering the circulatory system to differentiate into effector or memory thymocytes. These T cells express two cell-surface proteins, Fas and Fas ligand (FasL), which are both essential for apoptosis via the Fas pathway. Upon activation, thymocytes increase Fas/FasL expression -- the result is that over-stimulated cells are killed. This is essential for avoiding over-proliferation of thymocytes, and also for killing any self-reactive cells which avoided thymic selection.

T cell maturation

Traveling along chemical signals, thymocyte precursors migrate via blood from the bone marrow to the thymus. These cells have not yet rearranged their T cell receptor (TCR) genes and thus lack the T cell receptor (let alone CD3, CD4 or CD8); still lacking any characteristics of thymocytes, these immature T cells begin to divide furiously before individually undergoing four stages denoted double negative (DN) 1-4, named as such because the cells still lack CD4 and CD8 (CD4-CD8-). The four different DN steps -- taking a total of ∼3 weeks -- are described below, followed by the double-positive state (CD4+CD8+) and finally mature single-positive CD4+CD8- or CD4-CD8+ cells.

DN1c-kit+CD25-CD44highDouble-negative DN1 cells enter the thymus and proliferate as they become DN2 cells.
DN2c-kit+CD25+CD44lowTCRβ genes begin rearranging first, followed by TCR γ and δ (but not α) genes by ∼14 days.
DN3c-kit-CD25+CD44-In DN3 cells, TCR γ, δ and β rearrangement progresses. Immature thymocytes not expressing Notch proteins do not mature past DN3. At the transition from DN2 to DN3, γδ thymocytes become mature, undergoing very little more change; γδ cells frequently remain double-negative, and never become CD4+. DN3 αβ thymocytes halt proliferation, and β chains combine with a 33kD pre-Tα chain (aka gp33) and associate with CD3 to form the pre-T cell receptor (pre-TCR). The pre-TCR activates the following processes:
  1. With a productive β gene rearrangement, proliferation and maturation continues.
  2. Allelic exclusion, or suppression of further TCR β chain gene rearrangement.
  3. Makes the cells permissive for TCR α chain gene rearrangement.
  4. Induces progression to the double-positive state (CD4+CD8+).
DN4c-kit-CD25-CD44-The DN4 state occurs quickly after β rearrangement completes in DN3 cells. CD4 and CD8 coreceptors begin expression, leading to the double-positive state (CD4+CD8+)
DPCD4+CD8+The double-positive state (DP) involves rapid proliferation. This leads to a large population of T cell clones with identical TCR β chain rearrangements. Once proliferation stops, RAG-2 expression is activated and TCR α chain rearrangement occurs. This leads to tremendous diversity, as each TCR β chain rearrangement is now bound to a unique α chain rearrangement.
CD4+CD8-/CD4-CD8+DP cells proceed through thymic exclusion (described below), and surviving thymocytes expressing the αβ TCR-CD3 complex mature into single-positive CD4 or CD8 cells.

Thymic selection is a two-step process: positive selection, which induces apoptosis in thymocytes whose TCR cannot bind self MHC molecules; and negative selection, which induces apoptosis in thymocytes which bind self MHC molecules too well or in presence of a self peptide. Positive selection results in MHC restriction, and negative selection results in self-tolerance (meaning the thymocytes will not attack healthy self cells).

SelectionOverview
PositivePositive selection ensures the T cell only reacts to self MHC (MHC restriction) and takes place in the cortical region of the thymus, with immature thymocytes binding (or not) to MHC molecules on cortical epithelial cells. Upon binding to the MHC molecule, the thymocyte receives a protective signal that prevents apoptosis; if the thymocyte does not bind an MHC molecule, it proceeds with apoptosis.
NegativeOccurring after positive selection, negative selection ensures the T cell is does not react to self peptides. Dendritic cells and macrophages bearing Class I and II MHC molecules interact with thymocytes that bind self-antigen-MHC complexes or MHC complexes alone. Binding leads to apoptosis.

There are two proposed models as to how CD4+CD8+ cells mature into CD4+CD8- or CD4-CD8+ cells: the instructive model and the stochastic model. Neither model has been definitely proven nor disproven. The instructive model postulates that double-positive cells interact with either a Class I or a Class II MHC molecule, and are somehow signaled to differentiate into either CD4 or CD8 cells. The schotastic model postulates that repression of CD4 or CD8 is random and has nothing to do with TCR specificity. Only thymocytes whose TCR and coreceptor bind the same MHC molecule continue to mature.