Effector T Cells and Cell-mediated Cytotoxicity Flashcards
Cell mediated immunity
Recognize and eliminate cells that have been infected by viruses or transformed into cancerous cells
Involves antigen-specific effector cells, non-specific effector cells, and cytokines
Effector T cells
CD4+ helper (Th1) cells and CD8+ cytotoxic lymphocytes
Do not require CD28 costimulation (unlike naive cells) but can be costimulated by LFA-1 binding ICAMs on target cells
Higher levels of CD2 and LFA-1 to allow more efficient binding to target cells
Express CD44 (upregulated following TCR signaling), low CD26L and no CCR7
Traffick to tertiary lymphoid tissues and sites of inflammation
CD2 in effector T cells
Higher levels than in naive cells
LFA-1 in effector T cells
Higher levels than in naive cells
CD44 in effector T cells
Up regulated following TCR signaling
CD62L in effector T cells
Low levels
CCR7 in effector T cells
Not present
Prevents recirculation to secondary lymphoid tissue
Effector CD4+ T cells
Differentiate when under influence of polarizing cytokines and they come in contact with antigen
(to Th1, Th2, Th17, Tfh, Treg)
Have membrane and soluble effector molecules
Lymphotoxin
Membrane bound effector molecule of Th1 cell
Promotes macrophage activation by Th1 (along with IFNgamma)
CD40 ligand
Membrane bound effector molecule of Th2 cell
Allergic inflammation
Promotes B cell activation along with IL-4 with Tfh and Th2
IL17 + IL22 secreted by Th17
Promotes inflammation
IL10 + TGF-beta secreted by Treg
Down regulate cellular immune responses and inflammation
Effector molecules of CD8+ cells
Membrane-bound Fas ligand
Secreted IFNgamma, TNF and cytotoxins
Perforin, granzymes and Fas ligand mediate target cell destruction
IFNgamma and TNF enhance cell mediated immunity
CTL-mediated immune responses
Activation phase and effector phase
Activation phase of CTL mediated immune response
Stimulation of naive precursor CTL (CTL-P) Activated by TCR by foreign antigen/class I MHC complexes
Effector phase of CTL mediated immune response
Differentiated CTL engage and kill target cells
Differentiate into Tc1 or Tc2 cells
Licensing of antigen-presenting dendritic cells
- By Th1 or Th17 via antigen-class II MHC-TCR and CD40-CD40 ligand interactions
- Activation of TLR on dendritic cells by microbial products
Costimulation of CTL-Ps
By CD28-CD80/CD86 interactions
IL2 provided by CD4+ T cells
CD8+ T cells interacting with IL2 receptor
Activated CTL-P
Express high affinity IL2 receptors
Secrete IL2 ( not enough for autocrine growth/differentiation)
CD4+ T cell help is essential for development of memory CD8+ T cells
Memory CTL-P
When activated, may secrete sufficient IL2 for proliferation and differentiation into effector CTL
IL2 in CTL responses
CTL and Th1 are highly dependent on IL2 for proliferation and differentiation
Required in CTL for expression of genes coding for cytotoxic effector molecules that are stored in cytoplasmic granules
In absence of IL2, Th1/CTL undergo apoptosis
Tc1 cells
Differentiated CTL
Secrete IFNgamma
Kill by perforin and Fas ligand
Tc2 cells
Secrete IL4
Only small amount of IFNganna
Kill by perforin
CTL mediated destruction of target cells
- Conjugate formation
- Membrane attack
- CTL-target cell dissociation
- Target cell destruction
Conjugate formation
Only takes minutes
TCR recognition of forgein peptide presented by class I MHC on target cell
Stabilized by CD8 and LFA-1
TCR signaling causes transient increase in avidity for LFA-1 for ICAMS on target cell
Membrane attack
Golgi stacks and storage granules containing cytotoxins reorient in the cytoplasm and concentrate near the interface between CTL and target cell
CTL release storage contents in space between 2 cells
Perforin monomers insert into the target cell membrane and polymerize into pores that trigger endocytosis
Perforin
Undergo conformational change in presence of Ca to insert themselves in target cell membrane
Trigger endocytosis
Granzyme B
Binds mannose-6-phosphate receptors on the target cells
Complexes are internalized
Perforin allows granzyme B to be released from the vesicle into the cytoplasm
Cleaves substrates to initiate apoptosis
Fas pathway
Las ligand on CTL interacts with Fas on target cells leading to apoptosis
Independent of Ca
Caspases
Cysteine proteases that cleave proteins after an aspartic acid residue
Fas and perforin pathways result in activation of caspase 3, which causes activation of enconucleases that fragment nucleosomal DNA and proteases that disassemble cytoskeleton
Serpins
Expressed by CTL to protect themselves from granzyme B and perforin
Inhibit granzyme B
NK cells
Non-specific cytotoxic effector cells
Important in defending against viruses and cancer
Arise from same protenitor as T ells but do not develop exclusively in thymus
Express IL2Rbeta, CD2 and CD16
Not MHC restricted
Make IFNgamma
First line of defence
Activated by IL12 produced by dendritic cells
NK cells in effector function
Constitutively active
Cytoplasmic granules containing perforin and granzymes, express FAS ligand
Inhibitory and activating receptors
Kill cells with too low levels of class I MHC
Opposing signals model
Balance between activating and inhibitory signals determines whether or not an NK cell will ultimately kill the target cell
Inhibitory signals always override activation signals
C-type lectins
Recognize altered carbohydrate structures on virus-infected cells or cancer cells
Important category of activating receptor
Inhibitory receptors
Lectin-like inhibitory receptors, killer cell inhibitory receptors
Antibody dependent cell-mediated cytotoxicity (ADCC)
NK cells, neutrophils, eosinophils, monocytes and macrophages have receptors for Fc region of IgG
All of them (except NK) are activated through Fc receptors and release lytic contents of their lysosomes
NK cells activated through CD16, and use perforin and Fas pathways
CD16
Important activating receptor for NK cells
Activates ADCC
NKT cells
CD4+ and CD4- T cells that express NK cell markers and have an invariant alpha/beta TCR that interacts with CD1d on APC and epithelial cells Bridge adaptive and innate immunity Secrete IL4 and IFNgamma Have FasL effector function Help while adaptive response is forming
CD1d
On APC and epithelial cells
Present to NKT
Present lipid and glycolipid antigens
