SGD 23: IMMUNOLOGY 3

1. Using this figure, discuss how a CD4 T lymphocyte gets activated. ​(Matias)

● To activate a cytotoxic or helper T cell to proliferate and differentiate into an effector cell, and
APC provides two kinds of signals:
1. SIgnal 1 - is provided by a foreign peptide bound to an MHC protein on the surface of the
presenting cell. This peptide-MHC complex signals through the T cell receptor and its
associated proteins.
2. Signal 2 - is provided by costimulatory proteins, especially the ​B7 proteins​, which are
recognized by the co-receptor protein CD28 on the surface of the T-cell.
● The expression of B7 proteins on the APC is induced by pathogens during the innate response to
an infection. Effector T cells act back to promote the expression of B7 proteins on APC, creating
a positive feedback loop that amplifies the T cell response.
● Signal 2 is thought to amplify the intracellular signaling process triggered by signal 1. If a T cell
receives signal 1 without signal 2, it may undergo apoptosis or become altered so that it can no
longer be activated, even if it later receives both signals. This is one mechanism by which a T cell
can become tolerant to self antigens. (NICE TO KNOW ONLY)
● T cell receptor does not act on its own to transmit signal 1 into the cell. It is associated with a
complex of invariant transmembrane proteins called ​CD3​, which transduces the binding of the
peptide-MHC complex into intracellular signals. In addition, the CD4 nad CD8 co-receptors play
important parts in the signaling process.
● Once bound to the surface of an APC, a T cell increases the strength of the binding by activating
an integrin adhesion protein called ​lymphocyte-function associated protein 1 (LFA-1)​.
Activated LFA-1 now binds more strongly to its Ig-like ligand, ​intracellular adhesion molecule 1
(ICAM-1)​, on the surface of the presenting cell. The increased adhesion enables the T cell to
remain bound to the APC long enough for the T cell to become activated.
● The activation of a T cell is controlled by negative feedback. During activation process, the cell
starts to express another cell-surface protein called ​CTLA-4​, which acts to inhibit intracellular
signaling. It resembles CD28, but it binds to B7 proteins on the surface of the APC with much
higher affinity than does CD28, and when it does, it holds the activation process in check.
● Most of the T (and B) effector cells produced during an immune response must be eliminated
after they have done their job. As antigen levels fall and the response subsides, effector cells are
 deprived of the antigen and cytokine stimulation that they need to survive, and the majority die by
apoptosis. Only memory cells and some long-lived effector cells survive. (ADDITIONAL ONLY)

​ ttps://www.ncbi.nlm.nih.gov/books/NBK26827/
SOURCE:h

2. Discuss the functions of the effector CD4 T cells ​(Martin)

● Activated CD4 T cells function as cytokine producing helper T lymphocytes. CD4 cells produce
cytokines or membrane molecules that help activate CD8 T cells to become effector cytotoxic
cells and memory cells.
● The major function of CD4+ (helper) T cells is to provide help to other lymphocytes to mount an
efficient immune response. By secreting appropriate cytokines and expressing a variety of
co-stimulatory molecules, CD4+ T cells are required for the generation of high affinity antibody
responses to pathogens and for the formation of long-lived plasma cells and memory B cells
● Help from CD4+ T cells is required to generate memory CD8 T cells which are able to expand
upon secondary exposure to the pathogen
● By secreting a variety of cytokines, effector CD4+ T cells can also recruit other cells including
neutrophils and monocytes to the sites of infection.

3. Discuss the functions of the CD8 cytotoxic effector lymphocytes ​(Mercado)

● ​Activated CD8 cells function as cytotoxic T lymphocytes (also known as killer cells)
● The receptor proteins on the surfaces of the cytotoxic cells cause them to recognize Class 1
MHC-peptide complexes on the surface of infected cells, thereby killing them.
● The cytotoxic T cell secretes hole-forming proteins (Perforins) that punch round holes in the
membrane of the attacked cell, which lead to exocytosis of CTLs granules (through signal
transduction and with the help of granzymes) which enter target cells by receptor mediated
endocytosis, leading to apoptosis.
● The apoptosed cells are rapidly phagocytosed and eliminated
● Cytotoxic killer cells can pull away from the victim cells after they have punched holes and
delivered cytotoxic substances and then move on to kill more cells
● CD8 T cells also secrete IFNy which activates macrophages to destroy phagocytosed microbes
and enhances leucocyte recruitment
● Cytotoxic cells also play an important role in destroying cancer cells, heart transplant cells, or
other types of cells that are foreign to the person’s own body

4. A patient has pulmonary tuberculosis. Describe his immune response to this infection
(Mendoza J.)

When ​M. tuberculosis​ infects a person, it attacks the lungs' first-response immune cells, the
macrophages. The immune response by the macrophages involves a complex of four different proteins
called the "inflammasome." The main role of the inflammasome is to prepare certain immunity proteins in
the macrophages, which are called "interleukins." When ​M. tuberculosis​ infects the lungs, interleukins
from the macrophages are in the first line of defense.

But if it is left uncontrolled, this defense can also cause serious damage to the patient. To prevent this,
macrophages also release another group of proteins called "type I interferons." While interferons are
important for defending the body against viruses, when it comes to tuberculosis they actually help the
bacterium, thereby exacerbating the disease. And although the interleukin-inflammation part of the
immune response is rather well understood, the part involving interferons has been elusive.

The lab of Andrea Ablasser at EPFL, in collaboration with the lab of Stewart Cole, has now discovered
how ​M. tuberculosis​ carries out a subtle assault on our immune defenses. The key is a molecule called
cGAS, which is found in the lung's macrophages, and is part of a group of DNA-sensor molecules; in
short, cGAS patrols the inside of macrophages, and when it detects unidentified pieces of DNA, such as
those released by ​M. tuberculosis​, it triggers an immune response from the macrophages.

The tuberculosis bacterium uses a specialized secretion system to release its array of toxic proteins into
macrophages. But, strangely, it also releases small bits of DNA, which are detected by sensing systems
inside the macrophages, namely the inflammasome and cGAS. This causes macrophages to release two
types of proteins: interleukin-1, which fights the bacterium, and type I interferons, which end up helping it.

Ablasser's group used human and animal macrophages to study what happens when they are infected by
M. tuberculosis.​ ​What they found was that the bacterium passes DNA bits into the macrophages,
thereby tricking cGAS to signal the production of interferons, which reduce the immune response.
In other words, the bacterium tricks the macrophages to cut back on their defense against it.

But the researchers did not stop there. They also showed that it is possible to manipulate ​M. tuberculosis
in such a way that it can no longer activate the production of interferons through cGAS, while still keeping
the production of interleukin-1 -- and thus the body's immune response -- intact.

The study is the first to identify cGAS as a sensor for ​M. tuberculosis​ DNA, and also suggests that this
method of molecular manipulation applies to other bacteria that use specialized secretion systems to
infect cells. "Our work shows that tuberculosis is a far more sophisticated disease than previously
thought," says Andrea Ablasser, who is now working, among other projects, to identify the DNA pieces
that ​M. tuberculosis​ uses to trick macrophages.