Over the course of our life, our immune system will fight off countless infections from a variety of bacteria, viruses and parasites, in addition to protecting us from cancer and healing damaged tissue. It's a pretty remarkable system, accounting for over 85% of our genome, and yet is only possible because of a highly complex specialized cell types and backup response mechanisms.

The immune system is complex and involves many different cell types, some of which are represented here.

diversity of immune cells

Photo reprinted with permission of Macmillan Publishers Ltd. Nature Reviews Cancer® 2004.

Immunity cells constantly recirculate through the bloodstream and lymphatic system on the lookout for potential infections or tissue damage. An effective immune response depends on interactions between different types of immune cells in specific locations of the body. Immune cells then need to be able to travel from their sites of origin to the site of infection to carry out their jobs. Therefore, it can be said that the immune system relies on the ability of cells to move.

 

How do cells move?

One major method of cell migration is called chemotaxis, which is when a cell responds to chemical signals from the environment guide their movement. One prominent family of chemotactic factors capable of stimulating this process are called chemokines. Chemokines are small proteins produced by many cells in the body that exert their functions by binding to specific receptors. There are over 50 different chemokines and 18 chemokine receptors that have been identified so far, and a single chemokine can only bind to one or a few specific chemokine receptors. So, much like a lock and key, a chemokine key will only fit specific receptor locks.

chemokine receptors

Photo reprinted with permission of Macmillan Publishers Ltd. Nature Reviews Cancer® 2004.

The complex chemokine family (pictured above). Each receptor is represented by a colored bubble and may bind to one or several chemokines (listed next to each receptor).

Binding of the chemokine involved in chemotaxis to their receptors initiates signals inside the cell, causing changes to actin cytoskeleton which gives the cell its shape and allowing the cell to become motile. It does this by forming protrusions at the front of the cell (named pseudopods), which attach to surfaces, while retracting the back end, giving a crawling motion. This allows a cell expressing a particular chemokine receptor to move towards a site with higher concentrations of the respective chemokine.

Chemokines in immune responses

There are many different types of immune cells and each has specific capabilities; for example, B cells produce antibodies needed to fight off infection, while cytotoxic T cells can destroy cells infected with viral or bacterial pathogens. Different situations require different types of immune cells and the body needs a way to signal which kind it needs in each situation.

These different types of immune cells express different combinations of chemokine receptors, and this can influence what tissues they are recruited to, as well as the outcome of the infection or disease. The body doesn't always get it right through. Sometimes the immune response attacks our own cells inappropriately and this is known as autoimmunity. Some autoimmune diseases you may be familiar with include Type 1 diabetes, where the immune system attacks the pancreas and destroys the insulin producing cells, and rheumatoid arthritis, where the immune system causes too much inflammation in the joints.

Immune cells need to be in specific locations in order to fullfil their jobs. In this image (below) different immune cells types have been labelled with different colors to show their locations in a mouse spleen, one of the organs that play an important role in the immune system.

mouse immune cells spleen

Photo of melanoma (skin cancer) with immune cells in blue and green. Altering the expression of chemokine receptors on melanoma cells signals many immune cells to be recruited to the tumor. Photo reprinted with permission of Macmillan Publishers Ltd. Nature Reviews Cancer® 2004.
The scale of the immune response matters, as well. Too little leaves us vulnerable to infection. Too much, and it leads to autoimmunity. In cases of autoimmunity, the site of disease can express the chemokine CCL5, which leads to recruitment of cells expressing CCR5, a receptor for this chemokine. These CCR5-expressing cells include a type of T cell that is inflammatory and can enhance the autoimmune response, leading to increased disease. Allavena's research and that of others has shown that altering the expression or function of specific chemokine receptors in disease can prevent the recruitment of unwanted cell types and promote the recruitment of protective immune cells. The immune system must continually find the right balance to keep us protected without causing harm. Having the abillity to control the immune response can help autoimmunity and other immune disorders as well.

immune activation chop

Image Credit: Kevin Bonham

Chemokines in cancer immunity

The ability for clinicians to control the recruitment of immunity cells is a crucial part of cancer care. The body has innate ability to produce immune cells, which are capable of recognizing and destroying tumor cells (known as anti-tumorgenic cells). Immune cells can also suppress the immune response and allow the tumor to escape detection (known as pro-tumorgenic cells).

Recent research shows that by inhibiting a particular chemokine receptor on mouse melanoma cells, researchers were able to shift the immune cells towards an anti-tumorgenic response, which enhanced the immune response at the tumor site. The ability for researchers to use chemokines to prepare the immune system to efficiently attack the tumor eventually resulted in its complete regression.

Obviously for our health and well-being, it preferable to prep the immune system to recruit the type of cells that can attack the tumor and not other healthy cells. Their results provide further support that manipulating chemokine receptors are a useful tool perhaps in combination with another treatment in the fight against cancer. It would be helpful to know exactly how chemokines receptors control which types of cells are recruited so we can perhaps optimize their recruitment in the fight against cancer.

SOURCES

Allavena P, Germano G, Marchesi F, Mantovani A. Chemokines in cancer related inflammation. Exp. Cell Res. 317; 5, 10 March 2011, Pages 664-673.