Nature vs Nurture, in Immunology

You might know about the debate between nature versus nurture, which is probably one of the oldest arguments in the history of psychology. Essentially, this debate is about whether the development of an individual is defined by their genetic makeup or DNA ('nature'), or whether the environment or life experiences make up who they are as a person ('nurture'). There are certain traits we can thank our genes for, such as the colour of our eyes or pigment of our skin. But an individual's personality and behaviour are thought of as acquired traits, ones that you can learn as you grow up. In reality, you and I are who we are from a combination of both nature and nurture. 


But I'm not here to write about psychology (I'm an immunologist!). If you take this concept of nature versus nurture and bring it down to a microscopic level, this debate is currently happening in immunology. I'll explain.


In your body, there are several organs that serve different functions. Your skin provides a barrier to harmful pathogens in the outside environment, your lung helps you breathe, your heart pumps blood (you get the picture). Within each organ, there are tissue-resident immune cells called macrophages. Macrophages are 'big eaters' (the literal Greek translation), and their main role is to eat things or 'phagocytose' particles that are foreign. In addition to phagocytosis of pathogens, Langerhans cells (skin macrophages), can also migrate to the lymph nodes to quickly stimulate an adaptive immune response against foreign pathogens. In the lung, alveolar macrophages not only help keep the airways clean from dust and other particles you breathe in, but they also maintain an anti-inflammatory environment that prevents unnecessary inflammation. In the heart, cardiac macrophages can even conduct electricity (so cool!). Could you imagine a macrophage conducting electricity in your lung? Not really. It is clear that depending on the tissue type, macrophages have specialized (and very different!) roles to help the organ function properly. 


Is the function of a macrophage attributed to the genes they have? Or due to the tissue environment they live in? We have to first think about 1) where does a macrophage come from and 2) what makes them acquire their specific function.


In most organs, tissue-resident macrophages come from the yolk sac or fetal liver. These macrophages are usually given a special name, like Langerhans cells (in the skin), microglia (in the brain), alveolar macrophages (in the lung) or Kupffer cells (in the liver). These tissue-resident macrophages can sustain throughout your entire life by constantly self-renewing, or turning over. It's not surprising that since these macrophages live in one particular organ their entire life, they will have a unique function specific to that organ. That's similar to me living in one city and having one job for my entire life - I would become adapted to a particular lifestyle and it would be very unlikely I would change my day-to-day habits. That's not to say that I wouldn't react if someone broke into my house or if there was a natural disaster in my city. Of course, I would react. Tissue-resident macrophages also react immediately to danger, which brings in an army of immune cells to fight the foreign invaders and repair the damaged tissue. 


Unfortunately, not all macrophages will survive throughout the infection or injury. This is where another type of immune cell, the monocyte, comes into play. Monocytes are plastic immune cells, which means they can easily adapt to a particular environment. In fact, an important function of the monocyte is to replace tissue-resident populations following an inflammatory response and restore the homeostatic function of the organ. 


Here's where nature versus nurture becomes important. A monocyte-derived macrophage must be able to adapt to have the same function as the original tissue-resident macrophage, otherwise, the organ will fail to work. This has been studied by some research laboratories, and I'll talk about a specific example about alveolar macrophages in the lung.


Normally, alveolar macrophages replenish themselves unless the lung is under extreme conditions such as radiation (for example, radiation treatment for lung cancer), then blood monocytes are able to replace the resident population. A study by Gibbings et al. in 2015 compared the genes expressed by a monocyte-derived alveolar macrophage to an original tissue-resident alveolar macrophage using transcriptomics (looking at all the RNA transcripts that are produced by the genome of a specific cell type). Sure enough, monocyte-derived macrophages were nearly identical to the original resident cell (apart from about 0.1% of genes). If nature were the only factor, then monocyte-derived macrophages wouldn't be able to adapt to an organ's specific function. Therefore, the local environment within an organ (ie. nurture) is critical. You can read more about this study here.


Not all tissue-resident macrophages are self-renewing. In fact, dermal macrophages (in the dermis of the skin), osteoclasts (in bone), and intestinal macrophages (in the gut) come from blood monocytes. This highlights the fact that a single monocyte must be able to adapt to a specific niche, and local signals within the tissue will help dictate what a monocyte may become.


What are these specific signals? Well, this is an area of ongoing research, so we don't know all the answers yet. The function of monocyte-derived cells in a tissue-specific context is a really interesting field of research in immunology, and we are just beginning to understand what is really going on.