The human immune system is a complex network designed to protect the body from a vast array of threats, including bacteria, viruses, fungi, and parasites. This intricate defense system involves numerous specialized components that work together. Each component plays a specific role, contributing to the body’s ability to recognize and eliminate foreign invaders. The immune system’s precision allows it to mount appropriate responses to diverse challenges while maintaining overall health.
The Immune System’s Specialized Cells: T Helper Cells
Lymphocytes, a type of white blood cell, include T cells. T cells originate in the bone marrow and mature in the thymus, a small gland located in the chest. These cells direct other immune cells to ensure an effective immune response.
T helper (Th) cells, a specific subset of T cells, do not directly kill infected cells or pathogens. Instead, they activate and guide other immune cells, such as B cells, macrophages, and cytotoxic T cells, through the release of signaling molecules called cytokines. This orchestration is crucial for mounting a tailored immune response. For instance, Th1 cells primarily stimulate responses against intracellular pathogens like viruses and certain bacteria, while Th2 cells activate B cells to produce antibodies, which are important for fighting parasitic infections and allergens.
The TH17 Pathway: Its Discovery and Development
The discovery of T helper 17 (Th17) cells significantly advanced the understanding of immune regulation. Identified in 2005, Th17 cells are a distinct subset of T helper cells, separate from the Th1 and Th2 lineages. Their unique characteristic is the production of interleukin-17 (IL-17), a pro-inflammatory cytokine.
The recognition of Th17 cells stemmed from research into mouse models of autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE). These studies showed that IL-17-producing cells, driven by IL-23, induced disease, revealing a new lineage with specific roles in both protection and disease.
The differentiation of naive T cells into Th17 cells is influenced by several cytokines and transcription factors. Key signals for their development include transforming growth factor-beta (TGF-β) in combination with IL-6 or IL-21. The master regulator of this differentiation is the transcription factor RORγt (retinoid-related orphan receptor gamma t). RORγt activates genes for producing IL-17A and IL-17F, the signature cytokines of these cells. Additionally, other factors like RORα can also promote Th17 differentiation and upregulate IL-17 and IL-17F expression.
Balancing Act: TH17’s Role in Protection and Pathogenesis
The TH17 pathway plays beneficial roles in defending the body but also contributes to disease when dysregulated. Th17 cells primarily function in host defense against extracellular bacteria and fungi. They are abundant at mucosal surfaces like the gut, lungs, and skin, forming a first line of defense.
Th17 cells contribute to immunity by producing cytokines like IL-17A, IL-17F, IL-21, and IL-22. IL-17A and IL-17F stimulate cells to produce chemokines, which recruit neutrophils to infection sites. This recruitment clears extracellular pathogens. IL-22, another Th17 cytokine, helps maintain mucosal barrier integrity and promotes antimicrobial peptides. For example, in Klebsiella pneumoniae infections, Th17-mediated responses involving IL-17A and IL-22 restrict bacterial growth.
However, an overactive or improperly regulated TH17 pathway can lead to chronic inflammation and contribute to various autoimmune diseases. The proinflammatory activity of Th17 cells, while beneficial in controlled infections, can become detrimental when sustained or misdirected against the body’s own tissues. For instance, Th17 cells are implicated in psoriasis, a chronic inflammatory skin condition. In psoriasis, overproduction of IL-23 by skin cells stimulates Th17 cells to produce IL-17A and IL-22, leading to excessive keratinocyte growth and inflammation.
Similarly, in rheumatoid arthritis, an autoimmune disease affecting the joints, increased frequencies of Th17 cells and elevated levels of IL-17 and IL-23 are observed in patients. Th17 cells may contribute to joint damage by promoting inflammation and autoantibody production. In inflammatory bowel disease (IBD), including Crohn’s disease, Th17 cells play a proinflammatory role. The accumulation of T cells and higher IL-17 levels in the inflamed gut of IBD patients suggests this pathway’s involvement. Insufficient Th17 activity can compromise defense against certain pathogens, while excessive activity can drive debilitating inflammatory and autoimmune conditions.