Helper T Cells: The Commanders of the Immune System

Helper T cells (Th) are differentiated from Naïve CD4+ T cells after receiving specific stimuli (antigens, cytokines), including Th1, Th2, Th17 and regulatory T cells (Treg), etc. They provide helper functions to other cells of the immune system, especially antigen-presenting cells (APCs), such as macrophages, dendritic cells, and B cells, and play an important role in the activation and maturation of these cells.

A Brief History of T Helper Cell Subsets

The production of marker cytokines determines T helper cell subsets and functions. In 1986, researchers classified helper T cells into Th1 and Th2 cells based on different cytokine production and surface marker expression. Th1 cells produce the cytokines IFN-γ, IL-2 and TNF-α and are important for antiviral and antimicrobial immunity, while Th2 cells produce the hallmark cytokines IL-4, IL-5 and IL-13 and are important for resistance to extracellular pathogens such as helminth infections. In 1995,a class of immunosuppressive T cells constitutively expressing CD25 was discovered, later called regulatory T cells (Treg). A third subset, Th17 cells, was discovered in 2005 and its hallmark cytokines include IL-17A, IL-17F, and IL-22. Th17 cells are essential for antifungal responses and host defence against bacterial infection. The intestinal tract is rich in Th17 cells, which help to regulate the intestinal microbiota. In addition, follicular helper T (Tfh) cells were found to produce IL-21, which is essential for B-cell stimulation. Tfh cells may also produce IL-4, which is important for the conversion of immunoglobulin classes in B cells. Other 'unconventional' T helper subsets such as Th3, Tr1, Th9 and Th22 have also been defined, which can produce different cytokines.

Fig. 1 Timeline of major T helper cell discoveries (Saravia, J.; et al. 2019).

The Surface Markers and Secreted Factor of Th Subsets

Th Subsets	Surface Markers	Secreted Factor	Function
Th1	CD3, CD4, CD119, CD183 (CXCR3), CD195, CD218a, LT-βR, CD366	IFN-γ, IL-2, TNF-α, LTα	Mediates macrophage activation and kill intracellular pathogens.
Th2	CD3, CD4, CD119, CD193, CD194, CDw198, CRTH2, IL-33Rα, CD365	IL-3, IL-4, lL-5, IL-6, IL-10, IL-13, lL-25, IL-31	Mediates the activation of eosinophils, promotes the production of antibodies by B cells, and fights against extracellular pathogens.
Th3	CD3, CD4, CD69, LAP, CD122	TGF-β	It exerts immunosuppressive function by activating DCs.
Treg	CD3, CD4, CD25 (IL-2Ra), CD39, CD73, CD103, CD152 (CTLA-4), GARP, GITR, LAP	IL-10, IL-35, TGF-β	Exert immune suppression and immune tolerance by activating DCs, macrophages and B cells.
Tr1	CD3, CD4, CD49b, CTLA-4	IL-10, IL-21	Exert immune suppression and immune tolerance by activating DCs, macrophages and B cells.
Tfh	CD3, CD4, TCR α/β, CD84, CD126, CD150, CD154 (CD40L), CD185 (CXCR5), CD252, CD278, CD279	IL-6, IL-10, IL-21	Stimulation of B cell proliferation, differentiation and lg class switching in GCs.
Th17	CD3, CD4, TCR α/β, CD161, CD194, CD196, IL-23R	IL-17A, IL-17F, IL-21, IL-22, IL-26	Involved in inflammatory reactions caused by extracellular bacteria and fungi, etc.
Th9	CD3, CD4, TCR α/β	IL-9, IL-10	Play a role in fighting against extracellular parasites (such as nematodes) infection.
Th22	CD3, CD4, TCR α/β, CD194, CD196, CCR10	IL-13, lL-22	Promotes proliferation of keratinocytes and epidermal cells.

Reference

Saravia, J.; et al. Helper T cell differentiation. Cellular & Molecular Immunology. 2019, 16(7): 634-643.