Cell immune response Flashcards
Antigen presenting to naive t cells
T cell responses are initiated in the peripheral lymphoid organs, to which protein antigens are transported after being collected from their portal of entry
Dendritic cells that are resident in epithelia and tissues, capture protein antigens and transport them to draining lymph nodes
DC properties that make them effective APC for primary T cell responses
DCs are strategically located at common sites of entry of microbes and in tissues that may be colonized by microbes
DCs express receptors that enable them to capture microbes and respond to microbes
They preferentially migrate to T-cell-rich zones of lymph nodes through which naive T-cells circulate
Mature DCs express high levels of co-stimulatory molecules, which are needed to activate naive T-cells
DCs can ingest infected cells and tumor cells and present antigens from these cells to CD8+ T cells
Activation of T cells
Naive T cells circulate in secondary lymphoid organs
Native T cells acquire powerful functional capabilities only after they are activated
Antigen recognition by T cells leads to activation in form of:
-cytokin secretion
-proliferation (increase in the numbers of T cells of a specific clone)
-differentiation (of the naive cells into effector and memory T cells
Naive T cells activated by:
Dendritic cells
DCs present peptides:
-from endocytosed protein antigens in association with class II MHC molecules to naive CD4+ T cells
-from cytosolic and nuclear proteins displayed by class I MHC molecules to CD8+ T cells
Signals for T lymphocyte activation
Recognition of antigen is the first signal for the activation of T cells
CD4+ and CD8+ T cells recognize peptide-MHC complexes on APCs
Several other T cell surface proteins participate in the process of T cell activation
The second signal(s) for T cell activation is called costimulation
Signal 2 functions together with antigen (signal 1) to stimulate T cells
Signal 2
CD28:B7 works in cooperation with antigen recognition to promote the survival, proliferation, and differentiation of the specific T cells
CD40L:CD40 interaction enhances T cell responses by activating the APCs (B7 expression on DCs)
Regulation of T cell activation
T cell activation is influenced by a balance between engagement of activating and inhibitor receptors of the CD28 family
The inhibitory receptors of the CD28 family are CTLA-4 (cytotoxic T lymphocyte antigen 4) and PD-1 (programmed death 1)
CD28:B7 interaction is most important for initiating responses by activating naive T cells
ICOS:ICOS-ligand interactions are critical for helper T cell-dependent antibody responses
CTLA-4:B7 interactions inhibit the initial activation of T cells in secondary lymphoid organs
PD1:PD-ligand interactions inhibit the activation of effector cells in peripheral tissues
Therapeutic costimulatory blockade
CTLA-4-Ig is an approved therapy for rheumatoid arthritis and transplant rejection
CTLA-4-Ig is in clinical trials for the treatment of psoriasis and crohns disease
Inhibitors of the CD40L:CD40 pathway are also in clinical trials for transplant rejection and chronic inflammatory diseases
Antibodies against CTLA-4 and PD-1 are approved or are in clinical trials for the immunotherapy of tumors
Functional responses of T cell activation
Increase in surface molecule expression:
IL-2 secretion and IL-2Ra expression
Clonal expansion of T cells
Functions of IL-2
Stimulates the survival, proliferation, and differentiation of antigen-activated T cells
Increases production of IFN-y and IL-4 by T cells
is required for the survival and function of regulatory T cells
Therapeutic use of IL-2
Cancer
Canary pox virus
Clonal expansion of T cells
Proliferation results in increase in number of the antigen specific clones-clonal expansion
Clonal expansion: production of daughter cells all arising originally from a single cell, In a clonal expansion of lymphocytes, all progeny \share the same antigen specificity
Before antigen exposure, the frequency of naive T cells specific for any antigen is 1 in 10^5 to 10^6 T cells
After antigen exposure the frequency of CD8+ T cell specific for that antigen increases to 1 in 3 CD8+ T cells and 1 in 100 CD4+ T cells
Increase in surface molecule expression
CD69 (retention in lymph node), CD25 (IL-2Ra) (proliferation), CD40(activation of DCs, macrophages, B cells), CTLA-4 (Control of response), adhesion molecules, chemokine receptors
IL-2 secretion and IL-2Ra expression
- IL-2 is a growth, survival, and differentiation factor for T cells
- it is produced mainly by CD4+ T cells early after antigen recognition and co-stimulation
- It acts on the same cells that produce it or on adjacent cells
Differentiation of activated T cells into effector cells
Effector CD4+ cells express surface molecules and secrete cytokines that activate other cells (b lymphocytes, macrophages, and DCs)
Effector CD8+ cells are cytotoxic cells and kill infected cells
Decline of T cell responses
Elimination of antigen leads to contraction of the T cell response
Decline is responsible for maintaining homeostasis in the immune system
Decline is due to:
-cessation of co-stimulation
-cessation of growth factor production (IL-2)
-activation of sensors of cellular stress (such as the BH3-only protein Bim), which triggers apoptosis of T cells
Development of memory T cells
T-cell mediated immune responses to an antigen usually result in the generation of memory T cells specific for that antigen, which may persist for years, even a lifetime
Memory cells may develop from:
- effector cells along a linear pathway
- effector populations in divergent differentiation
Properties of memory T cells
increases expression of anti-apoptotic proteins (Bcl-2 and Bcl-XL) responsible for their prolonged survival (long lived cells)
Respond more rapidly to antigen stimulation than naive cells specific for the same antigen
The number of memory T cells specific for any antigen is greater than the number of naive cells specific for the same antigen
Are able to migrate to peripheral tissues and respond to antigens at those sites
Undergo slow proliferation- self-renewal for prolonged lie span of the memory pool
Maintenance of memory cells is dependent on cytokines (IL-7) but does not require antigen recognition
Role of CD4+ T cells in eradicating infections
Phagocytes with ingested microbes in vesicles
Cytokines secretion
Macrophages activation-> killing of ingested microbes
Inflammation, killing of microbes
CD4+ T cells responses involve:
Initial activation in lymphoid organs
Generation of effector and memory cells
Migration of effector cells to sites of infection
Elimination of infectious pathogens at these sites
Functions of CD4+ T cells are mediated mainly by cytokines
CD4+ effector T cells are classifies according to the cytokines they produce
Subsets of CD4+ Effector T cells
Three major subsets: Th1 Th2 Th17 follicular helper T cells
Development of Th1, Th2, and Th17 subsets
All develop from naive CD4+ T lymphocytes
The development process is sometimes referred to as polarization of T cells
Process can be divided into:
-induction
-stable commitment
-amplification
Th1 subset
Is induced by microbes that are ingested by phagocytes
Induced by microbes that activate phagocytes
Major effector T cell population in phagocyte-mediated host defense
The central reaction of cell-mediated immunity
Development of Th1
Differentiate in the presence of IL-12 and IFN-y produced by DCs, macrophages, and NK cells
IFN-y and IL-12 stimulate Th1 differentiation bby activating the transcription factors T-bet, STAT1, and STAT4
IFN-y is produced and amplifies the development
Functions of Th1 cells
Principal function of Th1 cells is to activate macrophages to ingest and destroy microbes
TH1 or follicular helper T cells stimulate the production of some IgG antibodies
Effector functions of Th1 cells are mediated through IFN-y
Why if IFN-y important for Th1 celsl
It activates macrophages to kill phagocytosed microbes
It acts on B cells to promote IgG2a subclass switching and inhibits switching to IgE
It amplifies the Th1 subset and inhibits the development of Th2 and Th17 cells
It stimulates expression of molecules that enhance antigen presentation (e.g. increase MHC I and II)
Therapeutic use of IFN-y in vetmed
Recombinant canine IFN-y (KT-100) in atopic dermatitis
hIFN-y against canine astrocytoma- clinical trials, gene therapy
fIFN-y in combination with fIL-2 and fGM-CSF- clinical trials fibrosarcoma, gene therapy
IFN-y gene therapy in canine brain tumors
TH1-mediated classical macrophage activation and killing of phagocytosed microbes
Th1 cells activate macrophages by contact-mediated signals delivered by CD40L-CD40 interactions and by IFN-y
Responses of activated macrophages: enhanced killing of phagocytosed bacteria
secretion of inflammatory cytokines
Increased expression of molecules requires for T cell activation
Th2 subset
Mediates phagocyte-independent defense
Eosinophils and mast cells play central roles in this defense
Important for the eradication of helminthic infections
Central to the development of allergic diseases
Development of Th2 cells
Differentiation is stimulated by IL-4 in response to helminths and allergens
IL-4, IL-5 and IL-13 are the main Th2 cytokines
Functions of Th2 cells
Stimulate:
- production of IgE
- mast cells
- eosinophils, these reactions eliminate helminthic infections
- alternative macrophage activation
Classical macrophage activation
M1
Microbial TLR-ligands and IFN-y
-ROS, NO, lysosomal enzymes -> microbicidal actions: phagocytosis and killing of many bacteria and fungi
-IL-1, IL-12, IL-23, chemokines -> inflammation
Alternative macrophage activation
M2
Monocyte, IL-13, IL-4
IL-10, TGF-B -> anti-inflammatory effects, wound repair, fibrosis
Th17 subset
Responsible for recruiting leukocytes and inducing inflammation
- critical for destroying extracellular bacteria and fungi
- contribute to inflammatory diseases
Development of Th17 cells
Stimulated by pro-inflammatory cytokines produced in response to bacteria and fungi
IL-1 and IL-6 initiate Th17 differentiation
IL-23 maintains proliferation and differentiation of Th17 cells
Functions of Th17 cells
Combat microbes by recruiting neutrophils to sites of infection
They produce IL-17 which induces neutrophil-rich inflammation
IL-17 stimulates the production of antimicrobial substances
Elimination of viruses by the immune system
Viruses cannot be destroyed by cells that lack microbicidal mechanisms
Viruses cannot be killed if they are in the cytosol where they are inaccessible to killing mechanisms
Ab neutralize before it enters cell- can be killed while inside cell
Kill the infected cell!
Main function of CD8+ T cells
The function of killing cells with viruses in the cytosol is mediated by CD8+ cytotoxic T lymphocytes (CTLs)
Other functions of CD8+ T cells
Eradication of tumors
Cytokine production
Critical roles in the acute rejection of organ allografts
Differentiation of CD8+ T cells into cytotoxic T lymphocytes
Involves acquisition of the machinery to kill target cells
- acquisition of modified lysosomes- granules that contain perforin and granzymes
- acquisition of the capability to secrete cytokines, mostly IFN-y
Differentiation is controlled by 2 transcription factors, T-bet and oesmodermin
Nature of antigen and antigen-presenting cells for activation of CD8+ T cells
Cytosol derived antigens can stimulate CD8+ T cells
Naive CD8+ T cells recognize antigen presented by MHC class I molecules on dendritic cells
Some APCs are not infected by the virus and do not endogenously synthesize viral antigen
- in such a situation the process of cross-presentation is used
- this process is also used to present tumor antigens
- only specialized subsets fo APCs can cross-present antigen (e.g. CD8+ DCs)
Role of helper T cells in CD8+ T cell differentiation
Naive CD8+ T cells may require CD4+ T cell help to differentiate into functional CTLs and memory cells
- if APCs are directly infected by the microbe, CD4+ T cell help may not be critical
- CD4+ helper T cells may be required for CD8+ T cell responses to latent viral infections, organ transplants, and tumors
In weak innate immune reactions CD4+ T cell help if required
Mechanisms of CD4+ T cell help to CD8+ CTLs differentiation
CD4+ helper T cells produce cytokines that stimulate CTL differentiation
CD4+ helper T cells enhance the ability of APCs to stimulate CTL differentiation
Role of cytokines: IL-2
Promotes proliferation and differentiation of CD8+ T cells into effector CTLs and memory CTLs
Role of cytokines: IL-12 and type I IFNs
stimulate the differentiation of naive CD8+ T cells into effector CTLs
Role of cytokines: IL-15
Important for the survival of memory CD8+ T cells
Role of cytokines: IL-21
Produced by activated CD4+ T cells induces CD8+ T cell memory
Effector functions of CD8+ cytotoxic T cells
CD8+ CTLs eliminate intracellular microbes mainly by killing infected cells
CD8+ T cells secrete IFN-y
- contribute to classical macrophage activation in host defense
- stimulates hypersensitivity reactions
Mechanisms of CTL-mediated cytotoxicity
CTL-mediated killing involves specific recognition of target cells and delivery of proteins that induce cell death
The process:
- antigen recognition (CD8 T cell has specific receptor for Ag; Ag presented by infected cell)
- activation of the CTLs
- delivery of the lethal hit that kills the target cells
- release of the CTLs
Recognition of antigen and activation of CTLs
To be efficiently recognized by CTLs, target cells must:
- express class I MHC molecules complexed to a peptide
- binds to the CD8 co-receptor
- bind intercellular adhesion molecule 1 (ICAM-1, the principal ligand for the LFA-1 integrin)
- form an immunological synapse
Two killing pathways
Perforin/granzyme-mediated cell killing
FAS/FASL-mediated cell killing
Perforin/granzyme-mediated cell killing
The major cytotoxic proteins in the granules of CTLs (and NK cells) are granzyme B and perforin
Target cell and CD8+ CTL interact
CTL releases granule contents into immune synapses
Perforin induces uptake of granzymes into target cell endosome and release into cytosol, activating caspases
Perforates cell membrane
Apoptosis of target cell
FAS/FASL-mediated cell killing
FasL on CTL interacts with Fas on target cell
Apoptosis of target cell
CTLs express a membrane protein called Fas ligand (FasL) that binds to the death receptor Fas, which is expressed on many cell types
Inhibition of CD8+ T cell responses: the concept of T cell exhaustion
In some chronic viral infections, the responses of CD8+ T cells are initiated but gradually extinguished-phenomenon called exhaustion
Due to:
-reduced production of IFN-y
-increased expression of multiple inhibitory receptors e.g PD-1
Because they dont react they die
Cytokine production by CD8+ Effector T cells
CD8+ T cells produce the macrophage-activating cytokine IFN-y
Examples of chronic viral infections in animals
feline viral rhinotracheitis
feline calicivirus
canine distemper
feline leukemia
