Helper T cells

Question 1

What is the function of CD4+T cells?

Answer 1

o Cells that help make antibodies
o Cells that fight infection independent of antibodies

Question 2

Do all helper T cells make the same kinds of cytokines?

Answer 2

• Helper T cells (Th) make different sets of cytokines good for fighting specific types of microbes

Question 3

How are different helper T cell subsets distinguished by?

Answer 3

• There are different Th subsets that can be distinguished by their cytokine expression

Question 4

What instructs the type of differentiation naive T cells will undergo to become a specific type of helper T cell and where does it happen?

Answer 4

• The type of microbe that is present during the activation of naïve T cells will instruct the differentiation of the T cell to the type of helper T cell that is best at defending against it
• Differentiation from naïve T cell to helper T cell happens in secondary lymphoid organs like the lymph node
  o Type of helper T cell is determined by the type of cytokine secreted by the antigen presenting cell which is detected by the naïve T cell cytokine receptor

Question 5

What are the 3 main types of helper T cells?

Answer 5

-Th1 cells
-Th2 cells
-Th17 cells

Question 6

What cytokines do Th1 cells make and what are they the most effective for?

Answer 6

o Th1 cells make cytokine interferon gamma, which activates macrophages that can kill intracellular microbes

Question 7

How do Th1 cells act?

Answer 7

 Macrophage has eaten a microbe it cannot kill on its own but it displays the antigen for the T cell to see->signals are generated which leads to interferon gamma production-> this will bind to the receptor for interferon gamma on the macrophage-> will lead to signal that activate the macrophage
 At the same time, another molecule is induced on the Th1 cell called CD40 ligand which will bind to CD40 on the macrophage
* In this case, the function of CD40L and CD40 interaction along with interferon gamma signalling is to allow the macrophage to be a better killer of the microbes living in its phagosome

Question 8

What disease states is excessive Th1 activation associated with?

Answer 8

 When there’s too much helper T cell activation as can happen with chronic infections, or if helper T cells are recognising our own antigens as per autoimmunity, there can be too much macrophage activation which leads to diseases
* Th1 cells are associated with chronic inflammatory and autoimmune diseases

Question 9

How does Th1 differentiation happen?

Answer 9

 Differentiation of this Th1 cell happens when intracellular microbes such as mycobacterium cause dendritic cells and natural killer cells to produce cytokines that will allow T cells to differentiate into Th1 cell

Question 10

What cytokines do Th2 cells make and what are they the most effective for?

Answer 10

o Th2 cells make cytokines IL-4, IL-5 and IL-13, which activate eosinophils and gut tissue to kill and expel worms

Question 11

How do Th2 cells act to achieve their function?

Answer 11

 Antigen presenting cell such as dendritic cell displays worm peptide->Th2 cell releases cytokines
* IL-5 is an activator of eosinophils (this cell has enzyme granules in it that are good at killing worms) which leads to expansion of eosinophil population and is their cue to release their granules to kill the worm
* IL-4 and IL-13 work on the gut to increase ability for people to get rid of intestinal parasites: they do this by increasing mucus production and gut motility which promotes worm expulsion

Question 12

What disease state is excessive Th2 activation associated with?

Answer 12

 Too much Th2 activation lead to manifestation of allergic diseases

Question 13

How does differentiation of Th2 cells happen?

Answer 13

 Differentiation of this Th2 cell happens when parasites such as Helminths will act on dendritic cells, mast cell and eosinophils to produce cytokines that act on T cells to differentiate into Th2 cells

Question 14

What cytokines do Th17 cells make and what are they the most effective for?

Answer 14

o Th17 cells make cytokine IL-17, which induces acute inflammation and leads to production of defensins to fend off extracellular microbes (including fungi and bacteria such as candida and staph respectively)

Question 15

How do Th2 cells act to achieve their function?

Answer 15

 Antigen presenting cell takes up microbes and presents them to Th17 cell-> Th17 will secrete cytokine

Question 16

How does IL-17 secreted by Th17 work?

Answer 16

 IL-17 works on activating vascular endothelial cells to promote recruitment of neutrophils and monocytes into the tissue
 IL-17 also works on further activating macrophages and monocytes so that they phagocytose the microbes and kill them
 IL-17 also works on epithelial cells by inducing them to produce small peptide antibiotics called defensins that are secreted into the lumen to bind to microbes and kill them

Question 17

What disease states is excessive activation of Th17 associated with?

Answer 17

 Th17 cells can cause disease such as chronic inflammatory diseases and autoimmune diseases

Question 18

How does differentiation of Th17 cells happen?

Answer 18

 Differentiation of this Th17 cell happens when extracellular bacteria and fungi activate dendritic cell to produce cytokines which will drive T cells to turn into Th17 cells

Question 19

Describe how activated helper T cells who don’t participate in the germinal center reaction help fight infection

Answer 19

• After activation, some T helper cells (Th) will stay in the lymph node to interact with B cells and help make antibodies, but others will leave lymph nodes and migrate to sites of infection
  o The migrating T helper cells will migrate out of the blood vessel into infected tissue using same mechanisms as neutrophils/monocytes do (following a pathway similar to acute inflammation)
• Th recognize microbial antigens displayed by macrophages and dendritic cells (who have digested these microbes) on the class II MHC molecules and secrete cytokines
• Cytokines made by Th act on other immune cells that kill the microbes such as macrophages, dendritic cells and neutrophils
  o The helper cell helps the immune cells
• Different Th subsets secrete distinct cytokines that can activate immune responses; these immune responses are specific to different classes of microbes

Question 20

What are granulomas and what causes them?

Answer 20

• Excessive activation of Th1 cells can lead to granulomas
  o Happens when Th1 cells try to wall off an infection
  o Granulomas are made up of macrophages, giant cells (macrophages fused together) and a rim of T helper cells

Question 21

What can granulomas cause and what disease states are they associated with?

Answer 21

o Granulomas can cause a lot of tissue damage and swelling
o Granulomas are present in tuberculosis, sarcoidosis, Wegener’s disease and Crohn’s disease

Question 22

What disease states is the inflammation and tissue damage that can be caused by excessive activation of Th17 associated to?

Answer 22

o This can happen in multiple sclerosis and inflammatory bowel disease such as ulcerative colitis
o Th17 also plays a role in psoriasis

Question 23

How does Th17 play a role in psoriasis?

Answer 23

 Excessive release of IL17 ramps up the inflammation
 Excessive release of IL22 (also released by Th17) leads to hyperproliferation of epithelium which leads to formation of psoriatic plaques
 In the case of psoriasis, Th17 cells promote the recruitment of neutrophils and more T cells to sites of inflammation, and also release cytokines that drive the overgrowth of skin cells.
 IL-23 is one of the cytokines involved in the Th17 pathway and it drives the differentiation of Th17 cells

Question 24

Identify psoriasis therapies and their function

Answer 24

o Adalimumab- Anti-TNF monoclonal antibody
o Cyclosporine- immunosuppressive small molecule drug
o Etanercept- TNF receptor Fc fusion protein
o Infliximab- anti-TNF monoclonal antibody
o Secukinumab- anti-IL-17A monoclonal antibody
o Ustekinumab- anti-IL-23 monoclonal antibody

Question 25

What are the two psoriasis therapies that target helper T cells?

Answer 25

o Secukinumab- anti-IL-17A monoclonal antibody
o Ustekinumab- anti-IL-23 monoclonal antibody