Carolina Holistic Medicine | Functional & Alternative Medicine | Charleston, SC

What are Helper T Cells (CD4+, Th1, Th2, Th17, and the Interleukins)?

A discussion of Th1 and Th2 would not be complete without the basic understanding of what these cells and what their function are.  Th Cells or Helper T-cells are derived from CD4+ cells (a part of the immune system’s basic cell structure). 

Helper T cells come in five major subsets and they are:

  • Th1 cells
  • Th2 cells
  • Th17 cells
  • Tfh cells
  • Treg cells

The difference between these subclasses or subsets are the cytokines that induce their differentiation; master transcriptional regulators; cytokines they produce and secrete.  We will discuss some of these cytokines in this article.

Cytokines are the hormonal messengers responsible for most of the biological effects in the immune system, such as cell mediated immunity and allergic type responses. Although they are numerous, cytokines can be functionally divided into two groups: those that are pro-inflammatory and those that are essentially anti-inflammatory but that promote allergic responses.

T lymphocytes are a major source of cytokines. These cells bear antigen specific receptors on their cell surface to allow recognition of foreign pathogens. They can also recognize normal tissue during episodes of autoimmune diseases. There are two main subsets of T lymphocytes, distinguished by the presence of cell surface molecules known as CD4 and CD8. T lymphocytes expressing CD4 are also known as helper T cells, and these are regarded as being the most prolific cytokine producers. This subset can be further subdivided into Th1 and Th2, and the cytokines they produce are known as Th1-type cytokines and Th2-type cytokines.

Why the need for these subsets?  Diverse types of pathogens and infections target different sites.  Some pathogens are small and target intracellular (inside the cell) while others are too big (such as helminth or worms) and too large for phagocytosis which is the term used to describe the ingestion and destruction of foreign invaders by our macrophages (think of the Pac-Man gobbling up those dots);  Some microbes are even resistant to macrophages and in this case we have a backup plan.  Helper T cells work by secreting cytokines which communicate with other cells of the immune system to activate the appropriate immune response to better defend our bodies against invading pathogens.

Th1 cells:  If there is an intracellular infection of a virus (or intracellular bacteria) let’s say; the dendritic cells of the macrophages secrete Interleukin 12 (IL-12).  The dendritic cell then migrates from the site of infection to a nearby lymph node where it presents the antigen (a part of the infectious organism) to a naive Cd4+ T cells.  Once the antigen is recognized more IL-12 is released to convert this CD4+ cell to that of a Th1 cell.  The next phase is where this new Th1 cell starts releasing Interferon-gamma (IFN-y).  Now IFN-y helps activate macrophages to phagocytize organisms and also stimulate the production of antibodies to help the macrophages identify and gobble up these invading microbes.  Compliment proteins are also enhanced, and these compliment proteins enhance phagocytosis by a process called opsonization. 

Complement protein mediated opsonization within the complement system is a part of the innate immune response. C3b, C4b, and C1q are important complement proteins that mediate opsonization.  After C3b has bound to the surface of an antigen, it can be recognized by phagocyte receptors that signal for phagocytosis.  The Th1 cells now secrete more IL-2 which promotes growth and differentiation of other T cells. 

Th2 cells:  the parasites fighter.  Interleukin 4 (IL-4) is released by macrophages and results in conversion of naive CD4+ cells to Th2 cells and thus in turn releases more IL-4, IL-5 and IL-13 to help stimulate B-cells to produce antibodies immunoglobulin-E (IgE).  IgE production is stimulated by IL-4, and activation of mast cells and eosinophils by IL-5;  IL-13 induces production of mucus in the intestines.  Large parasites cannot be phagocytized by the smaller macrophages, so TH2 will help by having IgE antibodies coat the surface of these parasites (worms for example). 

In the next steps we see how this system eliminates the pathogen.  Mast cells and eosinophils have receptors that bind to the Fc region of IgE bound to a parasite.  The invading parasite is then killed by enzymes released by the degranulation of these mast and eosinophils and result in the destruction of the parasite.  Increased mucus in the intestines induced by IL-13 will help expel the dead organisms from the body.  There is synergy with all these cells, interleukins and function with one goal in mind – rid the body of parasites and infectious organisms.  Th1 is so named as it was the first Helper T-cell to be discovered, likewise Th2 was the 2nd.  Th17 gets it name by the associated interleukin.

TH17 cells:  with the signature cytokine being IL-17 thus giving its name takes on microbes outside of the cell and also fungal infections.  IL-22 is also involved.  Fungi or extracellular bacteria (microbes outside the cell) are the targets of this helper T-cell.  IL-6 and Transforming Growth Factor Beta (TGF-B) will cause CD4+ cells to become differentiated into TH17 cells.  And IL-17 is released to recruit neutrophils to the site of infection.  This protects the body from fungal and extracellular infections.  However, overstimulation and molecular mimicry can lead to an autoimmune response.  A genetic mutation in the code that produces IL-17 will cause that individual to be more susceptible to these sorts of infections.  Both IL-17 and IL-22 help stimulate epithelial cells to produce antimicrobial peptides that make cells less susceptible to microbial invasion as another function of these cytokines. 

Regulatory T cells (Treg):  AKA suppressor T-cells, but now referred to at Treg cells. This cell cools down or regulates the activated immune system once the pathogen is eradicated.  It puts the brakes on or regulates the immune system so it does not go crazy.  An out of control immune system can wreak havoc on our bodies with manifestations we would not like of many named disorders and increased inflammation. 

This overactivity is involved in autoimmunity or Autoimmune (AI) disorders.  Treg cells are necessary in preventing autoimmunity.  Treg produce TGF-B and IL-10 which will help regulate the immune response and inflammation.  IL-10 is a potent inhibitor of macrophage function.  TGF-B will induce generation of more Tregs.

Tfh:  Follicular helper T cells:  IL-21 is associated with these cells and they help guide B cells to make appropriate antibodies to clear particular infections. 

Some people have suggested that immunization programs (and the subsequent reduction in microbiological exposure with super clean environments such as isolating kids from normal bacterial exposures) are responsible for the increasing incidence of atopy such as allergic rhinitis, asthma and atopic dermatitis (eczema). There is, however, no evidence that immunization causes atopy.

Moreover, this is not an argument that we should be exposing children to potentially fatal diseases again.  If experiencing native diseases reduces the incidence of atopy, then the task of immunologists must be to develop vaccines that mimic the positive effects of infection.  So back to the drawing board for vaccine researchers. 

The key take-home message here is that all needs to be in balance.  The balance and stability of Th1 and Th2 function is important; also keeping in control the TH17 and Treg cells is critical for a solid well-functioning immune system. 

It is all about balance and we see a relatively large imbalance in chronic illness. In those who do not recover from Lyme disease; who have horrible reactions to environmental molds, and those suffering from chronic inflammatory response syndrome (CIRS) it is all about an imbalance in the Helper T-cell system.

Written by: Yusuf Saleeby, MD

Ref: 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC27457/

https://www.youtube.com/watch?v=Qs1H5P0SaLU

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670773/

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