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Greetings,

       Immune system is a subject of interest to us for a variety of reasons. Vaccines is just one of them (but considered a major). However, here is an important point made by someone. Most of the vaccines that have been created are not the work of immunologist, but rather a microbiologist who by trial and error, comes across a potential antigen which may be significant. Further experiments, establishes how the immune system works. Such a reverse approach is often the case, though exceptions exist. Why not the other way around, you may ask. As a matter of fact, we don’t understand immune system fully and most of the time we have no clue of what the coordinates of immune protection for a given organism looks like.

      Immune system is also a subject of fascination because they are one of the key system that can link multiple systems. For example, it is known that immune cells share receptors and signaling molecules with neural cells and endocrine cells, thereby producing a three way connection. The field is referred as Psychoneuroimmunology. This means immune system may communicate with neural networks using neuropeptides, thereby significantly altering the neural functioning. There are other similar fields such as Psychocardioimmunology, Psychoneuroendocrine immunology (Link) etc. I can go on and on. Of note, the extraordinary feat of immune system is attributed to T cells.

      T cells come in a huge variety of flavours with each individual type accommodating a wide variety of inter related functions. The reason why I decided to post about T helper cells is, most of them know of Th1, Th2 and Th17 cells. Very few realize there are other types- Th9 and Th22 in the latest upgrade.

Fig 1: T Helper cells, well known subsets and
their functions. Source

     For starters, let me explain a little bit about T helper cells. As the name suggests these are cells that are designated to help kick start a process through signaling and cytokine support. During the T cell development they select either a CD4 lineage or CD8 lineage. Based on the selection they become known as CD4+ or CD8+. In their naïve state, they are receptive to different cytokines. The cytokines dictate what type of T helper cells are generated. Each type of Th cells have a set of signature cytokines that mediate the downstream effects. Table 1 defines types of T Helper cells (CD4+ type), and the most predominant cytokine they produce.

        There are a huge variety of immune phenotype of T cells. Most of them are involved in complicated circuits of interaction via molecular pathway. Th0 cells represent a naive group of cells that are receptive to cytokines and will differentiate into lineages based on the type of stimulation. There is a confusion in some literature as of where does Treg cells belongs. T regulator cells (CD4+ CD25+ Foxp3+) represent an important group of cells usually involved in dampening the response so as to control it. Though they arise from Th0 cells, it needs to be treated separate.

Table 1: T helper cell subtypes and characteristics.

    Th1 cells mediate Cell mediated Immunity, through activation of cytotoxic T lymphocytes. Th1 subset, secretes IL-2, IFN-γ, and TNF-β. Th2 cells mediate Antibody based response through helping activation of B cells. Th2 subset, secretes IL-4, IL-5, IL-6, and IL-10. In addition, cytokines produced by one subset negates the activity of other subset.

Fig 2: Th17 & Th22 cell differentiation.

Th17 cells form the 3rd subset to be discovered. Till recently Th17 cells were intensely investigated by immunologists. Naive cells on stimulation with IL-6 and TGF-β, induces IL-23 production. This further induces production of IL-17 & IL-22 which signal massive recruitment of neutrophils and cellular based immunity. This response elicits a massive set of immune response culminating in inflammation. The mechanism is also shown to possibly work in certain autoimmune conditions as well. More recently, it was identified that the same IL-6 based stimulation with other set of cytokines (especially TNF-α), also induces differentiation of another lineage the Th22 cells. They differ by massive production of Th22 cells.

      This points to an important question. What would be the functions of Th17 and Th22 cells which seem to be very much related. I don't have any definitive answer. But from published studies, I believe that Th17 cells are more associated with systemic response and Th22 is probably confined to the Skin homeostasis and inflammation.

Fig 3: Role of Th9 cells.

Source: Schmitt etal

    Not much is known about Th9 cells. They are the most recent members of the list. Th9 cells were described as yet another sepearte lineage of cells. They are proposed to differentiate in the presence of IL-4 and TGF-β. It has not been clear as to what are the properties of this cell. They are identified by their IL-9 secretion. They also produce IL-10. Experiments has shown that Th9 is important in Anti-parasitic immunity. In the similar lines, they interact with mast cells and also probably involved with allergy. Interestingly, they call upon Th17 response also.

     It would be interesting enough to know if there are more types of helpers. The point is immune system is a complicated circuit involving number of of cells. With  better techniques of identification, we probably will see more number of helpers. And for the existing one's, we still are not sure about how they help.

Korn, Thomas. (2009-04--1) IL-17 and Th17 Cells. Annual Reviews Immunology 27(1), 485-517. PMID: 19132915

Eyerich, S., Eyerich, K., Pennino, D., Carbone, T., Nasorri, F., Pallotta, S., Cianfarani, F., Odorisio, T., Traidl-Hoffmann, C., Behrendt, H., Durham, S., Schmidt-Weber, C., & Cavani, A. (2009). Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling Journal of Clinical Investigation DOI: 10.1172/JCI40202

Kara EE, Comerford I, Fenix KA, Bastow CR, Gregor CE, McKenzie DR, & McColl SR (2014). Tailored immune responses: novel effector helper T cell subsets in protective immunity. PLoS pathogens, 10 (2) PMID: 24586147

Schmitt E, Klein M, & Bopp T (2014). Th9 cells, new players in adaptive immunity. Trends in immunology, 35 (2), 61-8 PMID: 24215739