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T helper 3 cells (T_h3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen.^[1] T_h3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). T_h3 have been described both in mice and human as CD4⁺FOXP3⁻ regulatory T cells.^[2] T_h3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4⁺CD25⁻FOXP3⁻LAP⁺ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.^[3]

The function of T helper cells generally is to mediate the immune response by secreting cytokines and interacting with B-cells to enhance or inhibit their activity. This is of particular importance in the gut as this is where the highest load of foreign material, food, is present. T_h3 cells are involved in mucosal immunity and protecting mucosal surfaces in the gut from non-pathogenic non-self antigens. They mediate this non-inflammatory environment by secreting TGF-β and IL-10. TGF-beta promotes the class switch to low concentrations of IgA which is noninflammatory. IgA does not usually activate the complement system and is not involved with phagocytosis. T_h3 inhibits T_h1 and T_h2 cells.

T_h3 cells have different cytokine requirements for their growth from CD25⁺CD4⁺ T_reg cells. The survival of CD25⁺CD4⁺ T_reg cells is dependent upon interleukin 2 (IL-2),^[4] while in vitro differentiation of T_h3 cells is enhanced by TGF-β, IL-4, and IL-10.

Findings suggest that T_h3 cells are a different lineage from naturally arising CD25⁺CD4⁺ T_reg cells, but it is still unclear whether T_h3 cells are the same as induced T_reg cells because of the lack of a specific marker for T_h3 cells. It was previously shown that TGF-β was produced by intestinal dendritic cells,^[5]^[6] which has been considered to be the source of cytokines for the induction of T_h3 cells in the intestine. Additionally, since TGF-β production was induced by cytotoxic T-lymphocyte antigen 4 (CTLA-4), which is constitutively expressed on naturally arising T_reg cells,^[7] it is possible that TGF-β production from T_reg cells through CTLA-4⁻ mediated signaling may stimulate the differentiation of both induced T_reg cells and T_h3 cells.

T_h3 phenotype and secreted molecules

T_h3 cells are characterised as CD4⁺CD25⁻CD69⁺FOXP3-LAP⁺ cells. Unlike the well characterised T regulatory (T_reg ) cells, T_h3 cells do not express transcription factor FOXP3. There is a lack of specific transcription factor for full and reliable recognition of the T_h3 cell population.^[2]

Type II-lectin receptor CD69 is presented on cell surface shortly after activation. The presence of CD69 is not specific for T_h3 cells, since it is expressed on other lymphocytes, mainly subsets that are tissue resident.^[8] The latency-associated peptide (LAP) noncovalently bounds TGF-β and can be expressed by many cells of the immune system.^[9]

In tumors T_h3 cells can express lymphocyte activation gene-3 (LAG3). T_h3 cells produce vast amounts of TGF-β and to a lesser degree also the anti-inflammatory cytokine interleukin 10 (IL-10). In colorectal cancer T_h3 cells were described as 50 times more potent immune suppressors than the classical regulatory FOXP3⁺ T lymphocytes and their functions was mainly mediated by secretion of suppressive cytokines.^[10]

LAG3 acts as a negative regulator of T cell activation and function and can also be expressed on NK cells and other T cells, than T_h3. Because of its structural similarity to CD4, LAG3 can bind MHC class II molecules.^[11]

Activation and effector functions

T_h3 cells can be activated by TCR stimulation after the recognition of an antigen or induced from CD4+ T lymphocytes by TGF-β in the presence of IL-10 and IL-4 cytokines.^[12]

T_h3 participate in the regulation of the immune response via mechanisms independent on cell-to-cell contact. Secretion of anti-inflammatory cytokine TGF-β by T_h3 cells helps to maintain homeostasis in the gut and suppress exaggerated inflammatory and autoimmune responses in the body. TGF-β is a crucial cytokine for maintaining the naturally occurring T_reg cells, that suppress T_h1 and T_h2 immune functions.^[3] T_h3 cells can also directly suppress T_h1 and T_h2 cells by secretion of TGF-β and provide help to B cells towards IgA secretion.^[1]