T cell activation, differentiation and memory: chapter 11

central vs effector memory T cells

-*Tcm*: in secondary lymphoid tissues, longer life span, can differentiate into several different effector T cells. -*Tem*: at sites of infection (tertiary tissue), express original effector function after encounter with antigen

surface proteins used to distinguish naive, effector and memory T cells

-*naive T cells* have very low levels of activation marker (CD44) but need adhesion molecules such as CD26L and CCR7 (chemokine receptor) since it has never encountered antigen -*effector T cells* dont need adhesion molecules or chemokine receptors -difference in *central memory cells* and *effector memory T cells* is that effector memory T cells dont have chemokine receptors since they are very active. however central memory T cells need chemokine receptor since they are not as active

examples of effector T cells

-CD4+ subpopulations, different functions such as polarizing cytokines and effector cytokines. -some examples are TH1, TH2, TH17, Treg, TFH.

Cross regulation of T helper cell subsets

-GATA-3, T-Bet, reciprocally regulate differentiation of TH1 and TH2 lineages. -T-Bet can repress expression of TH2 factor GATA-3 and expression of cytokines -IL-4 can also repress the expression of T-Bet and TH1 effector cytokine IFN-y.

clonal anergy

-T cell non responsiveness -occurs if co-stimulation is missing -contributes to peripheral tolerance

Th1 differentiation

-TH1: activated by intracellular pathogen, ex viruses which interact with PRR cause APCs to generate IL-12 (polarizing). this binds to naive T cells and activates signal transduction pathway mediated by STAT4 that induces expression of transcription factor T-Bet. -T-Bet activates expression of effector cytokines such as IFN-y which define TH1 subset.

TH2 differentiation

-Th2 response is activated by extracellular pathogens. -parasitic worms bind to PRRs on B cells, which triggers polarizing cytokine IL-4. -this interacts with naive TCR and activates STAT6 pathway which upregulates transcription factor GATA-3. GATA 3 induces expression of Th2 effector cytokines such as IL-4, IL-4, IL-3

surface interactions responsible for T cell activation

-The interactions between a CD4 (left) or CD8 (right) T-cell and its activating dendritic cell. a dendritic cell is APC. it present to ClassII MHC or it can load internal peptides into MHC classI. -CD28 interactions with CD80/86 provide the require costimulatory signals. adhesion molecules (LFA-1/ICAM, LFA3/CD2) strengthen connection between the T cell and APC or target cell so that signals can be sustained.

some subsets of memory cells

-central memory T cells (Tcm) -effector memory T cells (Tem) -stem cell memory T cells ( Tscm) -tissue resident memory T cells (Trm)

TH1/TH2 subsets in disease ex. leprosy

-cytokines of TH1 cells such as IFN-y and TNF-B predominate in tuberculoid patients -cytokines of TH2 cells such as IL-4 predominate in lepromatous patients

effector cytokines

-cytokines secreted by T cell -leads to many outcomes

differences in properties of professional antigen presenting cells that induce T cell activation

-dendritic vs mac vs b cell -APCS are either resting or activated. -once activated they bind to PAMPS or antigens -dendritic cells are the best activators of naive T cells, maybe because they have very high levels of MHC, costimulatory molecules. -activated B cells interact best with differentiated Th cells that are specific for same antigen that activated them. -Macs play many roles, processing and distributing antigens in secondary lymphoid organs as well as interacting with effector cells in periphery.

how is CTLA4 used to treat autoimmune diseases?

-in the case of hyperactivity, CTLA-4 binding domain is used. it is soluble and looks like IgG but can bind to CTLA4. -APCs have B7 which you want to block CD28 binding from. in this case, CTLA4-Ig is going to bind to B7 and prevent CD28 from binding to it. -this is similar to competitive inhibition. the goal is to block destructive T cells from being active.

events that drive helper T subset polarization

-interaction of pathogen with PRR on APCs determined which polarizing cytokines are produced. polarizing cytokines that arise from APCs or other neighbouring cells interact with cytokine receptors and generate signals that induce transcription of master gene regulators, including genes for effector cytokines, which define the function of a subset.

how do T cells differentiate?

-naive T cells leave the thymus as CD4+ or CD8+, resting T cells (G0 of cycle). these cells havent encountered antigen and they circulate through blood and lymph, reside in secondary organs. -the primary response is when the T cell encounters antigen for the first time. this leads to activation and proliferation. these cells will differentiate into effector and memory cells

Tissue resident memory T cells

-non circulating, reside in peripheral tissue. -tissue specific properties (skin vs gut homing cytokine receptors)

how are T cells activated?

-once naive T cells are activated in the secondary lymphoid organs, it results in the generation of effector and memory T cells. T cell activation requires receptor-ligand interactions between the T cell and a dendritic cell as well as signals through cytokines that produced by activating APC. -cytokines such as IL2 get upregulated along with IL2R.

importance of IL2 in activation

-once naive T cells are activated, signal 1/2 cooperate to enhance transcription and stability of mRNA for IL2 and IL2-R which generates signals that enhance the entry of T cell into cell cycle (proliferation). most cells differentiate into effector helper cells, or cytotoxic cells. some become memory cells.

positive and negative costimulation

-positive: CD28 on T cells binds to CD80/CD86 on APC. this activates naive T cell. once T cell is activated, upregulate CTLA4. -negative: CTLA4 binds to CD80/CD86 on APC to increase competition since CTLA4 can bind much strongly. it decreases the response.

what are memory T cells?

-seen in adaptive immune response (secondary immune response) -they are not naive since they've encountered Ag before. -they are usually resting unless needed, they are easy to activate compared to naive T cells -they also have different cell surface proteins compared to naive and effector T cells.

why would you see certain T cells in certain places?

-skin and intestines: more resident memory T cells -no resident T cells in blood- need circulating T cells in blood. usually you will central memory T cells in blood and secondary lymph organs -T cells have many markers which determines its identity. each memory cell has it own marker profile which is used to compartmentalize cells. ex: *CD45* is only found in Stem cell memory T cells. then theres also *CD103* which is an epithelial binding antigen only found on Trm. early activation marker *CD69* is also only found on Trm.

stem cell memory T cells

-some properties of naive T cells -highly proliferative -high levels of co-stimulatory receptors -can differentiate into other T subsets

importance of immunological synapse

-successful T cell-APC interactions result in the stable organization of signalling molecules into an immune synapse. -the TCR/MHC-peptide complexes and coreceptors are aggregated in the central part of this synapse (central supermolecular activating complex csMAC) -interactions between adhesion molecules and their ligands help sustain signals generated by allowing long term cell interactions. these molecules are organized around the central aggregate forming peripheral supermolecular activating complex (psMAC)

what are T cell effector cells?

-these cells have specialized functions based on the type of immune response they need...consist of helper T cells, and cytotoxic T cells -they are derived from either naive, or memory cells after antigen activation. -very short lived

why are some polarizing cytokines same as effector cytokines?

-this is advantageous since there is more production of a specific cytokine. -can act on neighbouring cells to amplify a response

T cell activation 2 signal hypothesis

1. TCR, CD3 and CD4 or CD8 with MHC peptide -engagement of TCR 2. costimulation (not antigen specific)

T helper subtypes (CD4+ subsets)

1. TH1 -*polarizing cytokines* (IL-12, IFN-y, IL-18 -*effector cytokines*: IFN-y, TNF -*function*: Enhance APC activity, Tc activation, protection against intracellular pathogens, autoimmunity 2. TH2 -*polarizing cytokines*: IL4 -*effector cytokines*: IL4, IL5, IL13 -*function* protects against extracellular pathogens, IgE responses, allergies -*other subtypes*: TH17, Treg, TFH.

polarizing cytokines

causes T cell differentiation into subset -secreted by APC