Master Immune Regulators

T regulatory cells, also known as Tregs, are essential in the maintenance of immune homeostasis and self-tolerance. Naturally occuring Tregs (nTregs) are characterized by the expression of CD4, CD25 and FOXP3, which is a transcription factor important in the development of Tregs. In addition to nTregs, there are several distinct subsets of induced regulatory T cells (iTregs), including Tr1 and Th3. Tregs limit immune activation through a variety of direct and indirect interactions, many of which remain to be defined. Fully understanding Tregs will lead us to harnessing the capacity of these cells in order to develop strategies to limit and prevent autoimmune disorders, tolerance to transplantation, and potentially boosting immune activity against cancer cells.

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FOXP3 is a 50-55 kD transcription factor, also known as Forkhead box protein P3, Scurfin, JM2, or IPEX. It is proposed to be a master regulatory gene and more specific marker of T regulatory cells than most cell surface markers. Transduced expression of FOXP3 in CD4+/CD25- cells has been shown to induce GITR, CD103, and CTLA4 and impart a T regulatory cell phenotype. FOXP3 is mutated in X-linked autoimmunity-allergic dysregulation syndrome (XLAAD or IPEX) in humans and in "scurfy" mice. In human, unlike in mouse, two isoforms of FOXP3 have been reported: one (FOXP3) corresponding to the canonical full-length sequence; the other (FOXP3 δ2) lacking exon 2. The 150D antibody recognizes FOXP3 epitope encoded by exon 2 in humans, mouse and rat T regs. Clone 206D and 259D recognize a human FOXP3 epitope in the region of amino acids 105-235. Poly6238 recognizes both human and mouse FOXP3 and was raised against the N-terminal portion of FOXP3.

Treg Cell Markers

While FOXP3 is a definitive marker for functional Tregs, the need for identification and sorting of live Treg cells has led to characterization of a number of cell surface Treg markers. CD127 (IL-7Rα) is a marker that is down-regulated on Tregs. In conjunction with CD4 and CD25 staining, lowly expressing CD127 cells can be clearly delineated as Tregs (data shown right). Other functional Treg markers, CD39 and CD73, which are cell surface ecto-nucleotidase enzymes that contribute to the suppressive capacity of Tregs, have also been characterized. Further, activated functional Tregs have also been demonstrated to upregulate LAP (TGF-β1) and GARP, while down-regulating expression of CD45RA.

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Resting vs. Activated Tregs

Resting Tregs (rTregs) are CD45RA+, Foxp3lo, and CD4+. Activated Tregs (aTregs) are CD45RA-, Foxp3high, and CD4+. Cytokine-secreting non Tregs are CD45RA-, Foxp3lo, and CD4+. rTregs, when stimulated, can increase Foxp3 expression, convert to an aTreg, and proliferate. In vitro studies have shown that aTregs rapidly die following proliferation. Furthermore, aTregs inhibit rTreg conversion to aTregs, controlling the balance of active Tregs. Naïve T cells and Non Tregs are also capable of converting to aTregs, but less so than rTregs. Interestingly, Non Tregs have higher levels of Th17 factors (RORc, RORα, IL-17), showing a bias toward developing a Th17 phenotype.

Learn More: Miyara M., et al. 2011. Autoimmun. Rev. 10:744.PubMed.

Treg Pathways

Click on the image below to view a detailed interactive pathway map for Treg development and mechanisms of action.

Newest Treg Literature Using BioLegend Products

Stay up-to-date with the latest publications using BioLegend products for Treg research.


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