T Cell Immunity Flashcards
Define recent thymic emigrant (RTE) cells.
- naive T lymphocytes that egress from the thymus
- must go to secondary lymphoid organs and peripheral tissue to mature
- if activated before first pass, will behave inappropriately; most likely differentiate into Treg
Define adaptive immune response.
- initiated when naive T cells encounter their antigen on MHC of APCs
- TCR signaling => T cell activation
- effector T cells are generated
- act on target cells, not the pathogen itself
Differentiate between naive and memory T cells.
- expression: naive (CD45RA); memory (CD45RO)
- memory cells live longer
Differentiate between effector and central memory T cells.
- effector memory T cells: rapidly mature into effector cells upon reactivation => go to inflamed tissue; no CCR7
- central memory T cells: take longer to produce cytokines; remain in lymphoid tissue and circulate as naive T cells; CCR7
What signals are required for a successful T cell activation?
- activation: TCR recognizes peptide:MHC
- survival: costimulatory molecules (CD80/86, CD40L/40)
- differentiation: cytokine expression and secretion - dictates different T cell responses and fates
- activated T cells express the trimer of alpha, gamma, and beta chains to produce a high affinity IL-2 receptor (IL2Ra), also called CD25 (naive T cells only have gamma and beta; moderate affinity)
Describe the function and target pathogens of CD8 T cells.
Function - kill virus infected cells
Pathogens - viral; some intracellular bacteria
Describe the function and target pathogens of CD4 Th1 cells.
Function - activate infected macrophages; help B cells to produce antibodies
Pathogens - intracellular pathogens, microbes, extracellular bacteria
Describe the function and target pathogens of CD4 Th2 cells.
Function - provide help to B cells for antibody production; switching to IgE
Pathogens - soluble antigen, bacteria, helminth parasites, extracellular pathogens
Describe the function and target pathogens of CD4 Th17 cells.
Function - enhance neutrophil response; promote barrier integrity (skin, intestines)
Pathogens - fungi (candida), klebsiella, extracellular bacteria, eukaryotic pathogens
Describe the function and target pathogens of Tfh cells.
Function - help B cells in isotype switching and antibody production
Pathogens - all types
Describe the function of Tregs.
suppress T cell responses
List the following in reference to Th1 cells:
- inducer cytokines
- transcription factor
- signature cytokines
- inducer cytokines = IL12*, IL18, IFNg
- transcription factor = Tbet
- signature cytokines = IL2, IFNg, Lta
What disorders are impaired Th1 cell function associated with?
autoimmune disorders (diabetes)
What disorders are impaired Th2 cell function associated with?
immunopathology of asthma, allergies, dermatitis
What kind of immunity are Th17 cells involved with?
gut immunity
What is the immune response of Thf cells?
proliferation of B cells, differentiation of B cells into memory cells
What is the effect of TLR signaling?
cytokine expression
Where are TLRs found?
on surface membrane or intracellular membranes
What do TLRs respond to?
Different sections of pathogen molecules (ex: diacyl lipopeptides, triacyl lipopeptides, flagellum, LPS)
What is unique about TLR1, 6, and 10?
- ancient; inherited from neanderthal
What are TLR ligands called?
- PAMPs (pathogen)
- DAMPs (damage/danger)
- MAMPs (microbial)
Which T cells express TLR?
all TLRs are found on T cells (depends on if naive or mature)
Describe antigen uptake and presentation by macrophages and dendritic cells.
- pathogenic ligand binds to TLR
- phagocytosis of antigen and antigen processing
- antigen is presented on MHC molecules
What triggers the conversion of immature DC to mature? What are the characteristics of a mature DC?
trigger = antigen uptake
- decreased phagocytic capability
- upregulate MHC
- upregulate CCR7 to migrate to lymphoid
- upregulate costimulatory molecules (CD40, CD80/86)
- upregulate cytokine production of IL12 and Il18
Describe what happens when a mature DC meets its T cell in the lymph nodes.
- CCR7 expressing DC enters via afferent lymphatics and travels down the cortical sinus toward the paracortex where T cells reside
- T cells that do not find their antigen leave the lymph nodes via HEV
- T cells that find their antigen bind to DCs and differentiate
- differentiated T cells leave and migrate to the infected tissue
What immune response processes are Th1 cells involved with?
- cell mediated inflammation
- hypersensitivity delayed-type
- intracellular pathogen immunity
Describe the sequential events related to Th1 differentiation.
- TLR => antigen uptake => mature APC
- mature APC activates naive CD4 T cell (TCR:MHC, CD40/40L, CD28:CD80/86)
- APC upregulates release of cytokines IL12 and IL18
- IL12 stimulates T cell to upregulate TF Tbet, upregulates IL12R (positive feedback)
- Tbet upregulates IFNg, which further stimulates production of Th1 signature cytokines (IFNg, IL2, LTa)
- IL18 works to maintain and stabilize the Th1 response
Define IFNg. What cells produce it? Function?
Interferon-gamma is a proinflammatory cytokine
- produced by Th1 (signature), NK cells, CD8 cells
- activates macrophages by stimulating antigen processing, upregulation of MHC, and TLRs
- antimicrobial
- stimulates chemokine secretion
- suppresses Th2 and Th17
Define IL2. What cells produce it? Function?
Interleukin-2 is a T cell growth factor
- produced by Th1 cells and CD8 cells
- growth factor for T cells, particularly Tregs
- acts autocrine and paracrine
- moderate affinity IL2R (gb) vs high affinity IL2R/CD25 (abg)
- mutation in gamma chain causes SCID
Define LTa. What cells produce it? Function?
Lymphotoxin-a is part of the TNF family
- produced by Th1, CD8, NK, B and macrophages
- involved with maintaining lymphoid organ microenvironment and development
- implicated in rheumatoid arthritis and MS progression
Describe the downstream effects of Th1 signature cytokines on macrophages.
- IFNg activates macrophages in the infected tissue (without the need for antigen)
- macrophages produce tetrad proinflammatory cytokines (IL1, 6, 8, TNFa)
- proinflammatory cytokines have a wide range of autocrine, paracrine, and systemic effects to promote inflammation
Define IL-1. What cells produce it? Function?
IL-1 is a proinflammatory cytokine
- produced by macrophages and epithelial cells
- promotes neutrophil growth and emigration from the bone marrow
- facilitates host response to stress
- acts with IL6 to promote fever and depression in the CNS
- neuroendocrine effects on the adrenal glands
- stimulates antigen presentation on APCs
- IL1Ra antagonist
- works with TGFB, IL6, IL21, and IL23 to induce differentiation of Th17
Define IL6. What cells produce it? Function?
IL-6 is a classic proinflammatory cytokine
- redundancy with IL1: fever, acute phase protein (CRP)
- accelerates antigen activation and promotes response to IL2
- required for Th17 development
- may be required for Thf
- strong growth and differentiation effects on B cells in the presence of other B cell cytokines
- activates osteoclasts (bone mineral metabolism)
Define IL8. What cells produce it? Function?
IL-8 has chemotactic activity
- most potent recruiter of neutrophils to infection site
- produced by macrophages, neutrophils, endothelial cells (during intense inflammation)
What is a delayed-type hypersensitivity reaction?
- mediated by Th1 and CD8
- involved in diseases where macrophage activity is central
- tuberculin test to test for allergies
- explains reaction to mosquito bites
List Th1 chemokines, cytokines, and cytotoxins.
- chemokines = recruit macrophages to infection site
- cytokines = IFNg (vascular adhesion molecule expression, activates macrophages, increase inflammatory mediators); IL3/GM-CSF (promote monocyte differentiation from bone marrow HSC; monocyte surge in circulation will be attracted to site of infection where Th1 are present)
- cytotoxins = TNFa and LTa (local tissue destruction, increase adhesion molecules in local blood vessels)
What causes lesion of the infected tissue?
cytokines recruit phagocytes and plasma which causes a lesion
Define TNFa
Tumor Necrosis Factor - alpha is a proinflammatory cytokines
- potent macrophage activator
- activates endothelial homing and adhesion molecules
- upregulator of MHC and cytokines
- induces apoptosis and angiogenesis
- symptoms = flu to death
- clinically, we are able to manipulate its effects by producing anti-TNF antibodies (infliximab, adalimumab)
List the following related to Th2 cells:
- inducer cytokines
- transcription factor
- signature cytokines
- inducer cytokines = IL4
- transcription factor = GATA3
- signature cytokines = IL4, IL5, IL10, IL13
Describe the sequential events involved in Th2 differentiation.
- APC binds to naive T cell
- TCR:MHC and costimulatory signal start the expression of GATA3
- TCR:MHC also induces expression of high affinity IL2Ra and binding of IL2 further induces GATA3
- increase in GATA3 expression causes production of IL4 by the T cell, which further induces GATA3
- extracellular IL4 can also stimulate GATA3 (sources: mast cells, basophils, eosinophils, TCRgd)
What is the function of Th2 response?
If the APC that activates the naive T cell was a B cell:
- B cell activation
- B cell proliferation
- B cell differentiation into plasma cells
Define IL-4.
- initiates Th2 differentiation and growth
- produced by mast cells, basophils, eosinphils, TCRgd cells, and Th2 cells
- promotes B cell activation, proliferation, and differentiation
- may play a role in pathogenic autoantibodies
- plays a role in allergies (class switching from IgG to IgE)
- inhibits development of Th1
- anti-inflammatory (blocks Th1-mediated macrophage activation)
Define IL-5.
- Th2 signature
- eosinophil maturation
- recruiting eosinophils
- can drive allergy reactions
- can promote pathology Th2 autoimmune disorders (asthma)
Define IL-10.
- Th2 signature (also Thf, and iTregs)
- major driver of B cell differentiation and isotype switching
- inhibits Th1 differentiation
- inhibits dendritic cell function
- anti-inflammatory (inhibits production of IL1, IL12, and TNFa)
What can Il-5 and IL3 do?
- allergy
- asthma (Th2-mediated autoimmune response)
List the following in regards to Th17:
- inducer cytokines
- transcription factors
- signature cytokines
- inducer cytokines = TGFB, IL1, IL6, IL21, IL23
- transcription factor = RORgt
- signature cytokines = IL17, IL21, IL22
What cytokine is involved in amplifying the Th17 differentiation?
IL-21
What cytokine is involved in stabilizing the Th17 differentiation?
IL-21
What are the functions of Th17?
- organ-specific autoimmune disorders (MS, T1D, IBD, airway inflammatory disease)
Define IL-17.
- recruit and activate macrophages and neutrophils
- induces proinflammatory cytokines (IL6, IL8)
Define IL-21.
- enhances B cell function
- antibody mediated pathology (hyper IgE secretion)
What is hyper IgE secretion syndrome?
- hyper IgE secretion
- recurrent staph and fungal infections
- associated with IL21 and Th17
Define IL-22.
- protective gut immunity
- antimicrobial peptide expression
List the following in relation to Thf cells:
- inducer cytokines
- transcription factors
- signature cytokines
- inducer = IL6
- transcription = BCL6
- signature = IL6, IL10, IL21
What are functions of Thf cells?
- humoral response (assists B cells in producing antibodies)
- found in germinal center when fully matured and interacted with B cells
- recruited into the B cell zone by CXCR5 (further migration into germinal center)
What signals are required for Thf?
- IL6 in the paracortex by DCs
- costimulation by iCos (induced costimulator)
What are the 3 phases of cytotoxic T cell response?
- effector phase = 1-2 days after acute infection
- contracting phase = when source of infection dies, most T cells die by apoptosis (only 5-10% remain)
- memory phase = surviving cells create memory pool; can last up to 75 years
Where does CD8 activation occur?
near marginal sinus
- DCs and naive CD8s travel there
What is required for CD8 activation?
- costimulation of NK cell, DC cell, or plasma memory cell
- B7
- 4-IBBL (binds to 4-IBB on T cell)
- IL2, IL12
Describe the process of CD8 activation.
- NK cell recognizes virus
- NK cells produce IFNg=> DCs => upregulate CD40
- CD4 cells activate DCs => IL12, IL2, IFNg
- sustained CD8 response
Describe the initial interaction CTLs with infected cells.
- adhesion molecules
- TCR:MHC
- release of cytotoxic granules => apoptosis of infected cell
Describe the CTL method of killing.
- CTL express FASL, binds to FAS (CD95) on infected cell
=> caspase 8 => mitochondrial damage, activates other caspases, DNA fragmentation - cytotoxic granules
What is in the cytotoxic granules of CTL cells?
- perforin - forms pores in target cell
- granzyme B = apoptosis, caspase dependent and independent
- granulysin = cytolysis of bacteria, fungi, and parasites,
Describe unique characteristics of TCRgd cells.
- restricted variation (only 3 Vd, 7 Vg)
- antigen presentation via CD1A, B, C
- phosphor antigens (phospholipids, phosphoantigens
- TCRd1 = mucosal tissue functions
- TCRd2 = circulation
What are some human TCRgd disorders?
- HIV (increased d1, decreased d2)
- tuberculosis (decreased TCRgd)
- parasite infection (malaria, increases TCRg1)
What are 2 types of Tregs?
- natural = developed from DPs in thymus
- induced (iTreg) = developed in peripheral lymphoid
List the following for iTregs:
- inducer
- transcription factors
- signature
- inducer = TGFB, IL2
- transcription = FOXP3
- signature = TGFB, IL10
What are iTreg functions?
- maintain self tolerance
- regulate immune response
How do iTregs suppress?
- cell to cell contact
- IL10
How does cell cell contact with iTregs work?
bind to inhibitory receptors
- CTLA4
- PD1
How does IL10 work?
- reduces MHC Class II expression on APCs
- suppress costimulatory molecules and cytokines
- important in IBD and colitis
