Regulatory T-Cells


Regulatory T cells can be defined as a T cell population that functionally suppresses an immune response by influencing the activity of another cell type and (as described in Chapters 9 and 19 of Immunology IV) can occur either by cell-to-cell contact or by the elaboration of immunoregulatory cytokines, IL-10, and transforming growth factor (TGF)-β.

Several subsets of Treg, capable of controlling effector T cell responses, have been described (Chapter 7 of Immunology IV), including both naturally occurring Treg (nTreg) and induced Treg (iTreg) cells (Table 1). Although naturally occurring Treg cells originate directly from thymic precursors, induced Treg cells, Tregulatory 1 (Tr1) cells, and Th3 regulatory T cells differentiate from peripheral T helper cell precursors through the actions of different cytokines.

Over the past several years, several phenotypically distinct regulatory T cell populations have been identified that involve not only CD4+ T cell but also CD8+ T cell subsets. Shown in Table 2 are various regulatory T cell populations originating from the thymus and those arising in the periphery together with their suggested mechanisms of suppressive action. CD4+ regulatory T cells comprise a variety of subsets that are conceptually divided into three populations: (1) the classic regulatory CD4+CD25+FOXP3+ T cells are thought to be thymus derived, and are termed nTreg; (2) CD4+IL-10+FOXP3- regulatory T cells that are induced in vitro with various protocols or in vivo in response to exogenous antigen challenge and are termed adaptive regulatory T cells, iTreg, or Tr1; and (3) CD4+TGF-β+ T cells that are also induced Treg cells activated in the periphery in the context of oral tolerance and are termed Th3 cells.

Table 2.Various regulatory T cell populations

Regulatory T cellCharacteristic
nTregCD25+ FOXP3+ thymus-derived
Not dependent on IL-10 for biologic activity
Mediates self-tolerance/prevents autoimmune disease
iTregPeripheral-derived Treg cells 
Dependent on CTLA-4 for suppressive activity
FOXP3+ CD25+
TGF-β responsible for their induction
Th3Peripheral-derived regulatory T cells
Characterized by TGF-β production
Mediates mucosal tolerance/antigen-specific IgA production
Tr1Peripheral-derived Treg cells
FOXP3− or + at times
Characterized by IL-10 production
Possibly derived from Th1-like/Th2-like lymphocytes or naïve T cells
±CD25 expression (reflecting their effector function-activation)

*ILT3 = immunoglobulin-like transcript 3; **ILT4 = immunoglobulin-like transcript 3.

Cell subsetSuggested originSuggested mechanism of suppressive action
CD4+ T cell subset
 CD4+CD25+FOXP3+ (nTreg) cellsThymusCell-cell contact
 CD4+IL-10+FOXP3- ( iTreg or  TR1) cellsPeripheryIL-10
  CD4+TGF-β+ (TH3) cellsPeripheryTGF-β
CD8+ T cell subset
 CD8+CD25+ T cellsThymusTGF-β, CTLA-4
  CD8+CD28- T cellsPeripheryTargeting ILT3* and ILT4**
 CD8+CD62L+CD122+ T cellsNDND
  CD8+IL-10+ T cellsPeripheryIL-10

Treg are characterized by CD25 expression, CTLA-4 binding, and by the production of regulatory cytokines (IL-10 and TGF-β). Expression of CD25 on T cells is associated with natural regulatory function; CD25 is the α-chain of the IL-2 receptor and is also a marker of T cell activation. Forkhead boxP3(FOXP3) is the key regulatory gene in the development of CD25+ Tregs, which can be induced in the periphery, and their conversion into Tregs is dependent on TGF-β. Tr1 cells are a subtype of Tregs found in both humans and mice that are characterized by their low proliferative capacity, their production of high levels of IL-10, their production of low levels ofinterferon-gamma(IFN-γ), and their failure to produce IL-4. Th3 produce high levels of TGF-β and play an important role in the induction of oral tolerance. Tr1 cells seem to exert their suppressive activity due to their ability to produce high levels of IL-10 and TGF-β, whereas Th3 cells may act solely through the production of TGF-β, which has been claimed also to induce IgA class switching in vitro. The generation of active suppression or clonal anergy and/or deletion is due to the induction of TGF-β-producing Th3 cells that downregulate host responses.

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International Union of Immunological SocietiesUniversity of South AfricaInstitute of Infectious Disease and Molecular MedicineScience Education PrizesElizabeth Glazer Pediatric Aids Foundation