Lecture 16: Immune Activation, Helper Cells and Regulation Flashcards
What are the differences between properities of Class 1 and Class 2 HLA?
Class I HLA (endogenous)
- Surface structures found on virtually all nucleated cells
- Co-dominantly expressed
- Polymorphic genes (many alleles in the population)
- Present antigenic peptides to CD8 (cytotoxic) T cells
Class II HLA (Exogenous)
- Surface structures found on specialised antigen-presenting cells (APC) and B cells
- Co-dominantly expressed
- Polymorphic genes (many alleles in the population)
- Present antigenic peptides to CD4 (helper) T cells
(remember via (2 x 4) = 8 = (1 x 8)
Describe the difference in the peptides presented by Class 1 vs Class 2 HLA
Class 1:
- Self peptide
- Non-self peptide (due to viral infection)
Class 2
- Phagocytosed + processed antigenic material
What is the significance of polymorphic genes of HLA?
Different people express different peptides = different people are susceptible to different infections.
What are the structural differences between MHC1 and MHC2?
There’s more peptide showing in class 2
There’s a lot of presentation molecule around class 2- reason this is important is if we think about how T cells recognise peptides being shown to them.
- CD8 recognises the type of HLA*
- CD4 recognises the type of HLA (DQ,*
- The Receptors recognise the peptides*
*Important to know that it’s not just the peptides, but also the MHC that are being recognised by the T cells
Brief case notes:
Patient with defect in TAP genes have:
- Poor endogenous antigen processing
- Low HLA-A, B and C expression
- Few CD8 T cells, normal CD4 T cell numbers
- Recurrent respiratory viral infections
What does this tell us?
This tells us that:
- HLA class 1 is required for CD8 T cell development
- _CD8 T cell_s are important in viral infections
Name and briefly describe the structures involved in how we recognise our own peptide on Class 1 HLA (immune conversations = recognition)
Accessory moleucles (adhesions, costimulators, cytokines)
Consequence of antigen recognition is determined by context in which it occurs. Four types of factors affect this context:
-
Adhesion molecules link cells to other cells. Important in binding lymphocytes to antigen-presenting cells and also in directing lymphocytes and phagocytic cells to parts of the body where they are needed.
- Selectins (weak interactions)
- weak interactions
- direct cell traffic around body
- Integrins (strong adhesion)
- Selectins (weak interactions)
- Co-stimulator molecules pass signals between linked cells through surface-surface interactions to trigger or inhibit antigen-specific affects.
- Cytokines are soluble glycoproteins that signal cells expressing specific cytokine receptors (e.g. lymphocytes following antigen activation).
- Hormones are soluble molecules produced by the neuroendocrine hormone that modulate the response of antigen-activated cells.
What do B cells do?
B cell: A type of white blood cell and, specifically, a type of lymphocyte.
Many B cells mature into what are called plasma cells that produce antibodies (proteins) necessary to fight off infections while other B cells mature into memory B cells.
All of the plasma cells descended from a single B cell produce the same antibody which is directed against the antigen that stimulated it to mature. The same principle holds with memory B cells. Thus, all of the plasma cells and memory cells “remember” the stimulus that led to their formation.
Describe the Adhesion Molecules
Adhesion Molecules
1) Selectins (Weak Interaction)
- Selectin is important in first step of lymphocyte trafficking from bloodstream into tissues (_direct cell traffic around bod_y). It is also important in getting lymphocytes and APCs or lymphocytes and their targets together in order for other interactions (e.g. co-stimulation) to occur.
- Weak interactions (rapid association/dissociation)
- Direct cell traffic around body
- A bit like velcro
- Rapid association and dissociation meaning that adhesion is generally short-term and weak.
2) Integrins (Strong Adhesion)
- Versatile and diverse families of adhesion molecules important in cell-to-cell adhesion and cell to extra-cellular matrix adhesion.
- Strong adhesion
- Involved in maintenance of tissue integrity (hold cells in tissues together)
- Hold lymphocytes together for activation
-
Site-specific addressins involved in directing cells around the body
- Hereditary deficiency of some integrins can result in leucocyte adhesion deficiency (LAD). In this condition, leucocyte trafficking to sites of inflammation is impaired and patients are susceptible to recurrent pyogenic infections.
- These havev specific ligands for them which are a bit like antibodies.- referred to as immunoglobulin superfamily.
3) Immunoglobulin Superfamily (IgSF) Molecules
- IgSF is ligands for integrins.
- Contain Ig-like domains
4) Cadherins
- It is involved in embryogenesis, and tissue development.
- Homophilic interactions (like to like).
Neutrophil Migration From Blood To Tissues
When infection occurs in tissues, bacterial products can activate complement components, resulting in molecules that affect cells in blood vessel walls in the vicinity in two ways:
- Cells express more selectins and ligands for selectins which act as flags to show neutrophils where they are needed, and
- Spaces between the cells expand to allow neutrophils to squeeze between them more easily.
Describe the functions of Co-stimulators
Certain surface molecules are induced on antigen-presenting cells and lymphocytes only under particular conditions.
Co-stimulators modulate immune activation processes (what happens to lymphocytes when they recognise antigens).
- They are pairs of surface molecules expressed in cell-cell interactions
- B7 on APC -> CD28 on T cells
- CD40 on B cells -> CD40L on T cells
- They are expressed transiently.
- Modulate immune activation processes
One of the co-stimulators are pair of molecules called B7 on antigen presenting cells and CD28 on helper T cells.
- B7 is _not always present on surface of antigen-presenting cell_s. It is only induced when the antigens being presented are foreign and potentially dangerous.
- Helper T cells recognise antigens presented to their T cell receptors (TCR) by class II HLA molecules on surface of antigen-presenting cells. However, it will not respond to antigen unless CD28 molecules on T cells also interact with B7 molecules on antigen-presenting cells.
- If antigens are presented to T helper cells without B7 also being expressed on antigen-presenting cells, _T cells will not become activated t_o respond to that antigen. But instead, T helper cells will become paralysed. This is termed anergy and is one of ‘fail-safe mechanisms that prevent T cells from responding to self-antigens.
Another co-stimulator example involves interaction between CD40 on B lymphocytes and CD40L on helper T cells.
- When _B cells bind antigens t_hrough their surface immunoglobulins (sIg), they internalize them, _break them dow_n and present some of peptide fragments of their surface with class II MHC antigen-presenting molecules (from endoplasmic reticulum).
- This allows helper T cells bearing appropriate TCR to interact with them.
- As a result, B cell expresses CD40 co-stimulator molecules. If helper T cell expresses CD40-ligand (CD40-L) co-stimulator molecules on its surface, further interactions can take place leading to activation of the B cell to differentiate into antibody-forming cells.
(These are co-stimulators)
___on APC -> _______on T cells
______on B cells -> ______on T cells
B7 on APC -> CD28 on T cells
CD40 on B cells -> CD40L on T cells
If antigens are presented to T helper cells without ___ also being expressed on antigen-presenting cells, T cells will not become activated to respond to that antigen.
But instead, T helper cells will _________. This is termed _____and is one of ‘fail-safe mechanisms that prevent T cells from responding to self-antigens.
If antigens are presented to T helper cells without B7 also being expressed on antigen-presenting cells, T cells will not become activated to respond to that antigen. But instead, T helper cells will become paralysed.
This is termed anergy and is one of ‘fail-safe mechanisms that prevent T cells from responding to self-antigens.
Describe the Clonal activation of CD4 Helper T cells
Helper T cells require a specific interaction between their TCRαβ and antigen presented to them on c_lass II MHC_.
Interactions among other surface molecules, such as adhesion molecules and co-stimulator molecules are also necessary as discussed earlier.
Following activation, helper T cells produce a range of cytokine messenger molecules.
What are the 2 types of Checkpoint regulators?
Co-stimulators
- They are pairs of surface molecules expressed in cell-cell interactions
- B7 on APC -> CD28 on T cells
- CD40 on B cells -> CD40L on T cells
Co-inhibitors
- Interactions switch off response
- CTLA-4 -> B7
- PD-1 -> PD-L1 (programmed cell death protein 1)
- Some cancer cells turn on inhibitors
Following activation, helper T cells produce a_________________
Following activation, helper T cells produce a range of _cytokine messenger molecule_s and memory cells
What are the functions of Cytokines?
Functions
- Cytokines are small g_lycoprotein messenger molecules_.
- Usually s_ynthesized de novo._ Same cytokine may be produced by several different cell types (diversity of origin).
- Affect target cells via specific membrane receptors (exhibit very high affinity interaction with specific receptors). They can be:
- Paracrine (act locally, transient production, usually brief and self-limited), or
- Autocrine (act on cell secreting them), or sometimes
- Endocrine (distant action)
- They modulate immune and inflammatory responses. Same cytokine has many different effects (diversity of action).
