The adaptive arm of the immune system consists of many cells that work together to protect us from invaders like bacteria and viruses. One important player is the T cell. Broadly, T cells are divided into two major classes: cytotoxic T cells (CD8+) and helper T cells (CD4+), based on their function and the presence of CD8 or CD4 molecules, respectively, that decorate the cell surface. Functionally speaking, cytotoxic T cells directly kill infected or diseased cells while helper T cells instruct other cells of the immune system through the production of small molecules called cytokines. Cytokines act as chemical messengers by binding to receptor molecules on the surface of immune cells and instructing their next actions. For example, one cytokine might tell an immune cell to migrate into a virally-infected tissue, while a different cytokine might direct the cell to grow and proliferate in order to generate a larger arsenal of virus-fighting cells. While CD8+ T cell populations are relatively simple, there are many classes of CD4+ T cells. 

These various classes, or subsets, of CD4+ T cells are all derived from an immature, undifferentiated type of cell, aptly termed a naive CD4+ T cell. Upon recognition of a foreign substance (like part of a virus or bacteria), a naive CD4+ T cell becomes activated and differentiates into a mature CD4+ T cell belonging to one of the various subsets. These different flavors of mature CD4+ T cells each have a specific role during an immune response, and their development is influenced by the type of ailment a person is experiencing, whether it be infection, allergy, or disease. Depending on the ailment, different kinds of cytokines are produced in the surrounding environment and these are important in determining which subsets of CD4+ T cells arise. Some of these subsets include T helper 1, T helper 2, T helper 17, and T regulatory cells. These different subsets are classified by the specific cytokines they produce and have varying functions (Figure 1).

T helper 1 (Th1)

One major class of CD4+ T cells is T helper 1 (Th1) cells. Th1 cells are mainly induced upon infection with pathogens that like to live inside of cells called intracellular pathogens. These include viruses and certain bacteria like Salmonella or Listeria. In this setting, the infection induces the production of cytokine IL-12, which can drive a naive CD4+ T cell to become Th1. Th1 cells are historically classified as pro-inflammatory, meaning that they promote immune responses. More specifically, Th1 cells produce the cytokine IFN-𝛾, which activates other cells of the immune system such as macrophages, natural killer cells, and CD8+ T cells to either kill the invading pathogen or warn them to be on guard.  

T helper 2 (Th2)

Another major class of CD4+ T cells is T helper 2 (Th2) cells. Th2 cells are required to fight infection with parasites but are also involved in allergies. When your body encounters an invading parasite or an allergen, it induces the production of cytokine IL-4. When a naive CD4+ T cell interacts with IL-4, it can become Th2. Th2 cells produce many cytokines, including more IL-4 and IL-10. These then stimulate other cells of the immune system, namely eosinophils, basophils, and mast cells, to eliminate the parasite and stimulate B cells to produce infection-fighting antibodies. This response is also to blame for those allergy symptoms you experience. When your immune system is not tolerant to some outside substance such as pollen, dust, or mold, it also activates this response causing that sneezy, itchy allergy season so many of us experience. 

For a long time, it was understood that CD4+ T cells were separated into these two categories, Th1 or Th2. With technology advancement and ongoing research, this categorization proved to be a bit more complicated. Over the years, more and more subsets of CD4+ T cells have been discovered.

T helper 17 (Th17)

One of these newer subsets is T helper 17 (Th17) cells. Th17 cells are important to fight off bacteria and fungi that like to stay outside of cells, termed extracellular pathogens. Specifically, Th17 cells can provide protection at mucosal surfaces like the intestine. In these environments, the production of cytokines IL-1, IL-6, and TGF-ꞵ can cause a naive CD4+ T cell to become Th17. Th17 cells then go on to produce cytokines such as IL-17 and IL-22. These can recruit other immune cells such as neutrophils to kill the invading bacteria or fungi. Th17 cells can also promote the maintenance of our healthy tissues. More specifically, Th17 cells make sure that our tissues that contact the outside world, like the skin, lungs, or gut, remain intact and functional. This is very important, as this is the first line of defense to protect us from external threats like pathogens, chemicals, or allergens. On the other hand, Th17 cells have also been associated with autoimmune diseases. In this case, the Th17 cell responses would be harmful since it will be promoting immune responses that are attacking your own body.   

T regulatory cells (Tregs)

Another notable CD4+ T cell subset is T regulatory cells (Tregs). While there are several different kinds of Tregs that can form, overall, Tregs function to regulate the activation of the other T cell subsets. This is a system put in place to make sure that, in any given situation, T cell responses are controlled. Tregs can develop in response to the cytokine TGF-β. Tregs then go on to produce regulatory cytokines like more TGF-β or IL-10 to suppress T cell responses. Tregs can suppress inflammatory responses and also ensure that T cells that react to “self” or environmental substances don’t actually mount a response. In the context of inflammatory responses, Tregs are there to “shut off” the response once the job is done, like when an invading pathogen is cleared from the body, for example. It is important that the immune response stops once the problem has been solved. If left uncontrolled, the continued immune responses can start to damage your own body. 

Tregs are also responsible for shutting down any T cells that react with molecules from your own body or environmental substances to make sure there is never an inflammatory response to these. However, in some people, things can go wrong with this process. In some cases, genetic mutations or disease can create malfunctions in the immune system leading to autoimmune disease development. In other cases, increased or novel exposure to environmental substances can cause allergies to arise due to the immune system lacking the experience and tolerance for these substances. In these cases, T cells (like Th1  or Th2 cells) can become activated and, if Tregs fail to adequately control them, these activated T cells can attack the environmental substances or parts of your body to cause allergy symptoms or autoimmune diseases. 

While these are a few of the major subsets of CD4+ T cells, there are others, and as the years go on, more subsets may be discovered as scientific research technology advances.

Cover image: Ice Cream; CC BY-NC-ND 4.0