The adaptive immune system is responsible for mounting specific and lasting defenses against invading pathogens. T helper cells, identified by the CD4 surface protein, function as the immune system’s primary orchestrators, directing other cells how to respond to a perceived threat. These cells differentiate into distinct functional subtypes, allowing the immune response to be precisely tailored to the specific nature of the invading organism.
Defining the Roles of Th1 and Th2 Cells
T helper cells are divided into T helper 1 (Th1) and T helper 2 (Th2) cells. The Th1 lineage focuses on cell-mediated immunity, eliminating pathogens that live and replicate inside host cells, such as viruses and intracellular bacteria. The signature cytokine produced by Th1 cells is Interferon-gamma (IFN-γ).
IFN-γ activates macrophages, transforming them into effective killers capable of destroying infected cells or microorganisms. Th1 cells also promote cytotoxic T cells, which destroy infected body cells. This coordinated response ensures that the infection is cleared by focusing on the destruction of infected host cells.
In contrast, the Th2 lineage directs the humoral immune response, neutralizing threats outside of host cells, such as large extracellular parasites and toxins. Th2 cells produce Interleukin-4 (IL-4), Interleukin-5 (IL-5), and Interleukin-13 (IL-13).
IL-4 promotes the activation of B cells, leading to the production of antibodies. Th2 activity encourages B cells to undergo class switching, producing the antibody Immunoglobulin E (IgE). IL-5 and IL-13 recruit eosinophils and mast cells, which attack large parasitic invaders.
The Process of T Helper Cell Polarization
The decision for a naïve T helper cell to commit to the Th1 or Th2 pathway is a regulated process called polarization. This commitment is determined after a naïve T cell recognizes an antigen presented by an antigen-presenting cell. The initial cytokine environment dictates its fate.
Interleukin-12 (IL-12) is the primary signal that steers the naïve T cell toward Th1 differentiation. IL-12 is released by innate immune cells in response to intracellular microbes. This cytokine activates a signaling cascade that culminates in the activation of the master transcription factor T-bet, the genetic switch for the Th1 program.
Once T-bet is active, it promotes the expression of the IFN-γ gene. The resulting IFN-γ acts in a self-reinforcing loop by further upregulating T-bet expression, stabilizing the Th1 phenotype. Furthermore, IFN-γ has an inhibitory effect on the Th2 pathway.
Conversely, if the local microenvironment contains high levels of Interleukin-4 (IL-4), the T helper cell is directed toward the Th2 lineage. IL-4 activates a different signaling cascade that leads to the expression of the characteristic Th2 transcription factor, GATA3. GATA3 is the master regulator for the Th2 program, driving the expression of IL-4, IL-5, and IL-13.
The IL-4 produced by the newly differentiated Th2 cell strengthens the Th2 commitment and also works to suppress the Th1 pathway. This reciprocal inhibition between the two lineages ensures that the immune system commits fully to the most appropriate defense strategy.
Clinical Outcomes of Th1/Th2 Imbalance
When the delicate balance of T helper cell polarization is disrupted, the resulting skew toward one lineage can lead to chronic inflammatory states. A sustained dominance of the Th1 pathway, characterized by excessive production of IFN-γ, can lead to the immune system mistakenly attacking the body’s own tissues. This cell-mediated inflammation is characteristic of many organ-specific autoimmune disorders.
Conditions such as Type 1 Diabetes and Multiple Sclerosis are examples of Th1-driven pathology. Chronic inflammation in the digestive tract, such as that seen in Crohn’s Disease, is also strongly associated with an excessive Th1 response. The persistent activation of macrophages and cytotoxic T cells causes significant tissue damage in these chronic conditions.
An exaggerated Th2 response is the underlying cause of many allergic and atopic diseases. This imbalance leads to the body mounting a vigorous humoral response against typically harmless environmental substances, such as pollen or dust mites. The excessive production of IL-4 drives B cells to produce large quantities of IgE antibodies, which attach to mast cells.
Re-exposure to the allergen triggers the IgE-mast cell complex to release histamine and other inflammatory mediators, resulting in the immediate symptoms of allergy. Conditions like allergic asthma, allergic rhinitis, and eczema are marked by this Th2 dominance, which also involves the recruitment and activation of eosinophils via IL-5.