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T helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen. Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta ( TGF-β). Th3 have been described both in mice and human as
CD4 In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic ...
+ FOXP3 regulatory T cells. Th3 cells were first described in research focusing on
oral tolerance Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that would otherwise have the capacity to elicit an immune response in a given organism. It is induced by ...
in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+ CD25FOXP3
LAP A lap is a surface (usually horizontal) created between the knee and hips of a biped when it is in a seated or lying down position. The lap of a parent or loved one is seen as a physically and psychologically comfortable place for a child to ...
+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling. The function of T helper cells generally is to mediate the immune response by secreting
cytokines Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
and interacting with
B-cells B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
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. Th3 cells are involved in mucosal immunity and protecting
mucosal surfaces A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It is ...
in the gut from non-pathogenic non-self
antigens In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
. 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. Th3 inhibits Th1 and Th2 cells. Th3 cells have different cytokine requirements for their growth from CD25+CD4+ Treg cells. The survival of CD25+CD4+ Treg cells is dependent upon
interleukin 2 Interleukin-2 (IL-2) is an interleukin, a type of cytokine signaling molecule in the immune system. It is a 15.5–16 kDa protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible for ...
(IL-2), while '' in vitro'' differentiation of Th3 cells is enhanced by TGF-β, IL-4, and IL-10. Findings suggest that Th3 cells are a different lineage from naturally arising CD25+CD4+ Treg cells, but it is still unclear whether Th3 cells are the same as induced Treg cells because of the lack of a specific marker for Th3 cells. It was previously shown that TGF-β was produced by intestinal
dendritic cell Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. ...
s, which has been considered to be the source of cytokines for the induction of Th3 cells in the intestine. Additionally, since TGF-β production was induced by
cytotoxic T-lymphocyte antigen 4 Cytotoxic T-lymphocyte associated protein 4, (CTLA-4) also known as CD152 (cluster of differentiation 152), is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA-4 is constitutively expressed in re ...
(CTLA-4), which is constitutively expressed on naturally arising Treg cells, it is possible that TGF-β production from Treg cells through CTLA-4 mediated signaling may stimulate the differentiation of both induced Treg cells and Th3 cells.


Th3 phenotype and secreted molecules

Th3 cells are characterised as CD4+CD25 CD69+FOXP3-LAP+ cells. Unlike the well characterised T regulatory (Treg ) cells, Th3 cells do not express transcription factor FOXP3. There is a lack of specific transcription factor for full and reliable recognition of the Th3 cell population. Type II-lectin receptor CD69 is presented on cell surface shortly after activation. The presence of CD69 is not specific for Th3 cells, since it is expressed on other lymphocytes, mainly subsets that are tissue resident. The latency-associated peptide (LAP) noncovalently bounds TGF-β and can be expressed by many cells of the immune system. In tumors Th3 cells can express lymphocyte activation gene-3 (LAG3). Th3 cells produce vast amounts of TGF-β and to a lesser degree also the anti-inflammatory cytokine interleukin 10 (IL-10). In
colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...
Th3 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. 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 Th3. Because of its structural similarity to CD4, LAG3 can bind
MHC class II molecules MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, ...
.


Activation and effector functions

Th3 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. Th3 participate in the regulation of the immune response via mechanisms independent on cell-to-cell contact. Secretion of anti-inflammatory cytokine TGF-β by Th3 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 Treg cells, that suppress Th1 and Th2 immune functions.  Th3 cells can also directly suppress Th1 and Th2 cells by secretion of TGF-β and provide help to
B cell B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
s towards
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secretion.


References

{{Lymphocytes T cells