It is now widely accepted that several types of regulatory cells exist, some of which are induced in response to infectious challenge and some that are considered natural regulators. Regulatory T cells are pivotal in inhibiting inappropriate activation of cell and antibody mediated immune responses against self antigen as well as innate immune responses.

These regulatory T cell populations were first discovered in experimental aniaml models and subsequently indentified in humans.

The term “regulatory T cell” or “Treg” refers to a subclass of T cell that is capable of suppressing autoimmune reacitons and expresses the phenotypic markers CD4, CD25 and has no or low expression fo CD127. Treg also express FOXP3, however, CD127 expression has been demonstrated to correlate inversely with FOXP3 expression on CD4+CD25+ cells. (US Patent No: 10,300,090)

Definitions/Subsets of Regulatory T cells

Tregs can broadly be divided into T cells that appear to require antigen-specific, MHC-restricted stimulation, with subsequent secretion of cytokines that down-regulate immune responses, Tr1 and Th3 cells, which secrete IL-10 and TGF-B, respectively, or more innate reulatory cells that do not appear to require an in vivo adaptive immunization to observe their function, the CD1-restrcited NKT cells with invariant TCRs, “nonclassical” NK T cells with variant TCRs, and the CDr_CD25+ regulatory T cells.

Naive Treg: is a non-antigen experienced regulatory T cell that expreses the phenotypic markers CD4, CD25 and CD45RA as a primary cell, and does not express or has low expression of CD45RO and C127. Niave Tregs are advantageous because the cells have higher plasticity for responding to antigens than antigen experienced Tregs. In addition, naive T regs have increased longevity compared to antigen experience Tregs. (US Patent No: 10,300,090)

Memory Treg: is an antigen experienced regulatory T cell that is capable of providing suppressive effects on autoimmunity and expresses the phenotypic markers CD4, CD25, and CD45RO and does not express or has low expression of CD127 and CD45RA. 

Natural Treg cell (nTreg cell): It has been suggested that the term “thymus-derived Treg cell (tTreg cell) phrase should be used instead of “natural Treg”

Inducible regulatory T cells (Treg cells): It has been suggested that the term “in vitro-induced Treg cell (ITreg cell) should be used to clearly distinguish between those Treg cell populations generated in vivo versus those generated in vitro.

In vitro-induced Treg cell (iTreg cells): is the suggested terminology to show that the Treg cell populations are generated in vitro rather than in vivo. 

T helper type 3 cells (TH3)

CD4+CD25+ T cells

T suppressor cells (Ts)

CD4+CD25-, CD8+, CD+CD28-, NK-T cells: are of unknown.

How Tregs Suppress the Immune System:

T regs have many mechanisms to stop immune resposnes. In addition to making cytokines such as IL-10, IL-35 and transforming growth factor (TGF)-beta, they have CD25, which is a high-affinity IL-2 receptor alpha chain. IL-2 expressing T cells need to grow and proliferate, so immune resposnes are prevented when Tregs soak up IL-2. Tregs also have cytotoxic T lymphocyte associated protein 4 (CTLA-4), which is a receptor that binds to APCs and blocks costimulation. They also ahve the ectoenzymes CD39 and CD73, which convert floating adenosine triopsphate (ATP) into adenosine (a potent immunosuppressive), acting directly on T cells to stop them form killing beta cells. (Ferriera “using Regulatory T cells for treatment of Type 1 diabetes, Part 2” BioProcess International 21(5) March 2023).

Regulation of CD4+CD25+ T cells

Microbila induction of Toll like receptors reportedly blocks the suppressive effect of CD4+CD25+ TR cells, allowing activation of pathogen specific adaptive immune responses. This block of suppressor activity was dependent in part on IL-6, which was induced by TLRs upon recognition of microbial products.

In highly inflammatory environments, Tregs can transform into T cells. (Ferriera “using Regulatory T cells for treatment of Type 1 diabetes, Part 2” BioProcess International 21(5) March 2023).

Different molecuels will have different effects on Tregs. If, for example, a pateint takes steroids, low dose IL-2 or rapamycine, then those molecuels can interact with Tregs. Conventional T cells thrive on phosphoinositide (PI) 3 kinase, protein kinase B (AKT) and mammalian target of rapamysin (mTOR), whereas T regs do not. (Ferriera “using Regulatory T cells for treatment of Type 1 diabetes, Part 2” BioProcess International 21(5) March 2023).

Drugs which affect Tregs:

–Rapamycin: has immunoregulatory effects that promote Tregs to the detriment of conventional T cells. If you add rapamycin to a mix of Tregs and conventional T cells, it will inhibit the P13-kinase, AKT and mTOR. Conventional T cells will stop growing and die wehreas the Tregs survive just fine. (Ferriera “using Regulatory T cells for treatment of Type 1 diabetes, Part 2” BioProcess International 21(5) March 2023).

Engineered Tregs:

Chimeric antigen receptor (CAR) and T-cell receptor (TCR): are being used to build target specifcity into Tregs. This has application for example for patients undergoing solid organ transplantation or hematopoietic stem cell trnsfer as well as type I diabestes, reheumatoid arthritis, multiple sclerosis, hemophilia and inflammatory bowel disease. (“Treg engineers take aim at autoimmunity” Nature Biotechnology, 39, 2021).