11- T cell activation and differentiation
T cells bind antigen presented on MHC I and II (self and foreign) in the secondary lymph organs (lymph nodes, spleen) = ACTIVATION
Once activated, the T cell proliferates (clonal selection) and differentiates (CD8 Cytotoxic cell AND CD4 Helper T cells)
Cytotoxic CD8+ T cell
Helper CD4+ T cell
Type I, II and 17
Regulatory T cells
Follicular B Helper T cells
Learning Objectives
Describe the two main signals needed to activate a naive T cell and the difference between costimulatory and coinhibitory signals
Describe the extracellular influences (polarizing cytokines) and intracellular influences (master gene regulators) that drive differentiation of naive CD4+T cells into helper T cell lineages, as well as what distinguishes the various lineages functionally (effector cytokines)
Outline the major differences between Type I and Type II immune responses and understand how distinct helper T cell subsets contribute to the responses
Identify the four main memory T cells subsets, understand their functions, and speculate about their origin
Key Terms
Naive T cell: non-activated mature T cell
Quiescent: resting dormant nonactive cell
HEV: high endothelial venule in lymph nodes where T cells enter
T cell zone: area in lymph node where T cell binds to peptide-MHC complex on dendrite and is activated and differentiates
Clonal expansion: proliferation
Polarization: differentiation into effector cell subsets
Two signal T cell activation hypothesis: 2+1; requires 3 types of signals to activate a naive mature T cell
Cognate antigen signal: direct interaction between TCR and peptide that signals T cell activation
Costimulatory signals: CD28 and ICOS
B7: also known as CD 80/86 on APC
Immunological synapse: TCR interaction with MHC peptide complex creates a light connection to organize signaling molecules
Central supramolecular activating complex (cSMAC): contains all the required molecules to activate T cells
Peripheral supramolecular activating complex (pSMAC): contains the adhesion molecules to reinforce adhesion between T cell and pAPC
CD3: intracellular signaling receptor molecule
CD4/CD8: coreceptors that recognize MHC class I and II
Anergy: state of non-responsiveness; inactivation
pAPC: professional antigen presenting cells, B cells, macrophages and dendritic cells
CCR7: chemokine receptor allows dendritic cells to migrate to SLOs
Superantigen: binds TCR and MHC II that are not compatible in the absence of signal 2 (costimulatory receptor signals) and activates T cell
Type I Helper T cell: regulate immunity to intracellular pathogens (Type I immunity)
Type II Helper T cell: regulate immunity to multicellular parasitic worms (Type II immunity)
Type 17 Helper T cell: regulate immunity to extracellular pathogens (Type II Immunity)
Regulatory Helper T cell: inhibitory cells that regulate immune response
Follicular Helper T cell: B cell activation and isotype immunoglobulin polarization
Master gene regulator : regulates expression of effector cytokine profiles unique to each Helper T cell subtype
IL-5: effector cytokine secreted by Type II TH cells that activates granulocytes
IL-4: effector cytokine secreted by Type II TH cells that activates IgE B cell isotype expression
Cross regulation: effector cytokines produced by one Helper T cell subset inhibits the development of the other subsets
IL-6: effector cytokine that determines THREG and TH17 polarization released by extracellular infections of the mucosa epithelial layers
Key Concepts
Notes
Naive T cells are mature T cells that emigrated from thymus into secondary lymph organ and has not been activated by antigen binding.
Mature T cells will circulate in the blood to two secondary lymph organs:
different lymph nodes in search of specific MHC complex to bind to. They enter lymph nodes through HEV (high endothelial venules) and browse T cell zone to find specific MHC. If not found they leave through efferent lymphatic vessel into other lymph nodes, thoracic duct drains into superior vena cava and reenters blood circulation to travel to other lymph nodes in other body areas.
spleen: enters through blood and exits through blood
After clonal expansion, most T cells die because they are not needed. Those that remain after infection is cleared remain as memory T cells residing in different anatomical parts in the body (lymph nodes, tissues, blood).
During the activation of T cells in the T cell zone of the SLOs, 3 signals are required to activate naive T cells. Cognate antigen signal is a direct interaction between the TCR and peptide MHC complex that activates the T cell. Costimulatory signals from pAPC activate only naive T cells. Local IL-2 cytokine signals.
The light connection between TCR and MHC peptide complex is known as the Immunological synapse. This is composed of two regions, the central and peripheral supramolecular activating complexes. In the cSMAC, the main components of T cell activation are located, TCR, costimulatory molecules, coreceptors and CD3 intracellular receptor molecule. In the pSMAC, there are adhesion molecules that ensure a prolonged adhesion of the pAPC to the T cell for chemokine signaling.
The main chemokine involved in T cell activation is IL-2. Naive T cells have a low affinity IL-2 receptor composed of Beta and Y (gamma) chains. When the T cell is activated, a third alpha chain is expressed that forms a high affinity IL-2 receptor on the T cell.
During clonal expansion of T cells, memory cells are generated in each step. There is stem, central and effector memory T cells that have different capabilities of proliferation depending on the specificity. As T cells differentiate and become more specialized, they lose the potential to self-renew.
The first signal in the activation of T cells is the cognate antigen signal that binds TCR and MHC complex. The second signal is the costimulatory signal that activates naive T cells and can be costimulatory or coinhibitory. The third signal is cytokine signaling of IL-2. Clonal anergy in the periphery SLOs (secondary lymphoid organs) is present when the second signal (costimulatory receptor signaling) is absent. This allows are tolerance of self.
pAPCs provide signals 1 and 2 for T cell activation, primarily dendritic cells. This is because they are able to migrate to secondary lymph nodes and have costimulatory receptors that are able to activate naive T cells. Dendrites recognize pAMPS through PRRs on the surface and phagocytose the pathogen. This induces the expression of B7 costimulatory receptor, CCR7 chemokine receptor that allows them to migrate to secondary lymph nodes, and MHC II presentation. They are then able to activate naive T cells through TCR binding on MHC-peptide complex.
Superantigens are present on pAPCs that bind on incompatible TCR and MHCII that allow for inappropriate activation, proliferation and differentiation of T cells. These are present as exogenous or endogenous depending on whether a viral gene integrated in the mammalian genome and expressed the superantigen OR a bacteria presented the superantigen on the surface. These are common in food poisoning.
Helper T cell subsets each carry out different immune responses and secrete unique cytokine profiles that regulate immune responses. Polarizing cytokines regulate the diffentiation of Helper T cells into one of 5 subsets. Each subset is distinguished by polarizing cytokines that differentiate the T cell into a subtype, master gene transcription factor, and effector cytokines that are produced by the cell to carry out different functions.
Questions
Where does a T cell develop and mature? Thymus and in circulation
Where does a recent thymic T cell emigrate to? Secondary lymph organs (nodes and spleen)
Describe a quiescent cell: Minimal metabolism, resting cell, condensed DNA into chromatin (nondividing), little cytoplasm and low transcription activity. This is because it is resting and not actively proliferating.
Explain how T cells browse for MHC complex in the lymph node: enter lymph node from blood into HEV, browse T cell zone, if no MHC found, exit through Efferent lymphatic vessel into nearby lymph nodes, if still not found, exits thoracic duct into superior vena cava to enter blood and travel to farther lymph nodes in the body.
Explain how T cells browse for MHC complex in the spleen: enters through blood and exits through blood.
Do Helper T cells and follicular Helper T cells migrate to infected areas in the body? No. They are only involved in activating B cells, so they do not migrate to infection areas. Only Cytotoxic T cells migrate.
What can T cells differentiate into in the T cell zone of a lymph node? Follicular B Helper T cell, Helper T cell and Cytotoxic T cell
What are the main steps that occur when a T cell encounters their antigen? Stops migration, takes residence in SLO, proliferates through clonal expansion and differentiates into effector T cell subsets
What does costimulatory signal CD28 bind? B7 (CD 80/86) on APC
What does costimulatory signal ICOS bind? ICOS-L
Which activation signal is not required for memory T cells? Costimulatory signal; able to be activated by macrophages and costimulatory signals are present on pAPC dendritic cells only
What type of cell is the only cell that can activate naive T cells? Dendritic pAPC cells because it has all the costimulatory ligands
What type of cytokines activate naive T cells? Interleukin 2 cytokines
Which types of signaling does cytokine perform on naive T cells? paracrine and autocrine signaling
What is the purpose of cytokine signaling in naive T cell activation? proliferation and polarization
What is the purpose of cognate co-stimulatory signaling in naive T cell activation? allows for naive T cell activation that can only be achieved by dendritic pAPC
How does the pAPC know what the T cell needs to differentiate into? pAPC are phagocytes that present the pathogen antigen on the MHC complex to the TCR to signal the expression of the correct T cell subset by secreting the specific polarizing cytokines
Once a T cell is activated, what happens on the T cell that allows for higher affinity for chemokine signaling (proliferation)? the synthesis of a third subunit IL-2 receptor alpha chain that interacts with beta and gamma chains
What is the purpose of the IL-2 chemokine signaling in T cell activation? proliferation.
What receptors facilitate and negatively regulate activation of naive T cells? costimulatory and coinhibitory receptors
What are examples of coinhibitory receptors? Which one is commonly binded by cancer cells? CTLA-2, BTLA, and PD-1; PD-1 commonly binds ligands expressed on cancer cells
coinhibitory receptors regulates activation of T cells through what mechanism? it regulates clonal expansion by negatively regulating the secretion of IL-2
What is the purpose of peripheral clonal anergy? promotes tolerance to self in the periphery SLOs
What is the purpose of central clonal anergy in T cell development? builds tolerance to self, however, peripheral clonal anergy is still necessary
How is peripheral clonal anergy achieved? inactivation of self-reactive T cells because co-stimulatory signals are absent on non-pAPC cells that are necessary to activate naive T cells AND co-inhibitory receptor regulation
What cells provide the necessary signals for T cell activation? pAPCs (macrobphages, dendrites, B cells); specifically dendritic cells
Why are dendritic cells a better pAPC for T cell activation? they have costimulatory receptors that can activate naive T cells; they are able to migrate to secondary lymph organs
Why don’t macrophages and B cells play a major role as pAPC’s in T cell activation (and dendritic cells are)? neither are able to activate naive T cells due to absence of costimulatory receptors; macrophages stay at site of infection and are able to activate memory T cells; B cell receptors are antigen specific and bind to the same antigen
How are dendritic cells able to migrate to secondary lymph nodes? expression of chemokine receptor CCR7 that binds to the ligand in the lymph node
Which regions do superantigens bind to? MHC II alpha chain (light) and TCR Vb (variable Beta) chain
What are the dangers of superantigens? activates a huge amount of T cells with the same Vb region that it binds to which leads to a dramatic amount of inappropriately activated T cells and cytokine secretion (proliferation and polarization)
How are superantigens found in the body? viruses and bacterial genes that integrate into mammalian genomes or are found on the surface of pAPCs
Which cells present superantigens? pAPCs
Superantigens commonly result in which disease? food poisoning
Name the 5 subsets of Helper T cells: Type I, II, 17, Regulatory and Follicular
How are Helper T cells distinguishable by subset? polarizing cytokines induces the expression of a master gene regulator that regulates the expression of the effector cytokine profiles produced by each unique subset
Which cells are activated by Helper T cells Type I? What is the effector cytokine? macrophages and CD8+ cells; IFN-gamma
Which cells are activated by Helper T cells Type II? What is the effector cytokine?Eosinophis, mast cells and basophils; IL-4,IL-5,IL13
Which cells are activated by Helper T cell Type-17? What is the effector cytokine?Neutrophils; IL-17
Which cells are activated by Follicular Helper T cell? What is the effector cytokine? B cells; IL-21
What are the functions of the effector cytokines released by TH Type II? IL-5 activates granulocytes. IL-4 activates IgE formation because it is more suited to fight parasitic infections.
What determines the cross regulation of TH1 and TH2? effector cytokine inhibition
What determines the cross regulation of TREG and TH17? IL-6
Which subsets of T helper cells are grouped together due to cross-regulation? TH1/TH2 and THREG/TH17
How are memory T cells identified? 4 cell surface markers
When are memory T cells generated? At the beginning of T cell activation
Whare the three types of memory T cells? permanent residents, Effector and Central