Regulatory T Cell and Forkhead Box Protein 3 as Modulators of Immune Homeostasis

Abstract

The transcription factor forkhead box protein 3 (FOXP3) is an essential molecular marker of regulatory T cell (Treg) development in different microenvironments. Tregs are cells specialized in the suppression of inadequate immune responses and the maintenance of homeostatic tolerance. Studies have addressed and elucidated the role played by FOXP3 and Treg in countless autoimmune and infectious diseases as well as in more specific cases, such as cancer. Within this context, the present article reviews aspects of the immunoregulatory profile of FOXP3 and Treg in the management of immune homeostasis, including issues relating to pathology as well as immune tolerance.

Keywords: forkhead box protein 3; immune homeostasis; immunotolerance; regulatory T cell lymphocytes; regulatory status.

Figure 1

Genomics and structural organization of forkhead box protein 3 (FOXP3). The FOXP3 gene has 11 exons and is located on the short arm of the human X chromosome in Xp11.23 position. This gene encodes a protein FOXP3 with 431 amino acids structurally organized in the repressor domain, the N-terminal portion; zinc finger (ZnF) and leucine zipper (Zip), in the central portion; and forkhead domain, in the C terminal portion.

Figure 2

Forkhead box protein 3 (FOXP3) signaling cascade. The induction of FOXP3 is initiated following the presentation of peptides derived from autoantigens (PDAA) through the interaction of the T cell receptor with major histocompatibility complex of class II (TCR-MHC II) on antigen-presenting cells (APC). Alternative stimuli include cytokines transforming growth factor (TGF)-β, interleukin (IL)-2, and metabolites derived from the intestinal microbiota (DMNM). FOXP3 interacts with chromatin remodeling factors (TIP60 and HDAC7), which facilitates the dynamics with target genes and prevents the interaction of transcription factors [nuclear factor kappa B (NF-kβ) and nuclear factor of activated T cells (NFAT)] with activating cytokines cell response genes (IL-2, IL-4, and interferon-γ), but promotes the expression of genes linked to regulatory T cell (Treg) activation [CD103, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and CD25], highlighting the double FOXP3 function as a transcriptional repressor and activator.

Figure 3

Phenotypic diversity of regulatory T cell (Treg). There are two separate subsets of Treg. The first population of resident cells that is formed along the thymopoiesis and express constitutively markers including CD25, CD4, cytotoxic T-lymphocyte-associated protein 4, and glucocorticoid-induced TNF receptor family related protein. The second subset is formed by a peripheral Treg (pTreg) population that induces regulatory phenotype in the peripheral lymphoid organs, under specific conditions, antigenic stimulus, or suppressor cytokines.

Figure 4

Regulatory T cell (Treg) action mechanisms. Tregs induce immune suppression by four classical mechanisms: the contact cell-to-cell is mediated by surface markers cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and lymphocyte activation gene 3 (LAG-3) that interact, respectively, with molecules CD80/86 and MHC II on the target cells, regulating cell function. AMPc is also a mediator of this mechanism, which is released directly through the gap junctions and inhibits the proliferation and differentiation of the target cell. Cytokine production, in which transforming growth factor (TGF)-β and interleukin (IL)-10 modulate the activation and function of Treg. Competition for growth factors, in particular IL-2, the constitutive expression of CD25 on Treg, and their deprivation induce target cell to apoptosis through the B cell lymphoma 2 protein (Bcl-2)/BIM pathway. A fourth mechanism is found in lineages Type 1 Treg that secrets Granzyme B (GZB) and perforin (PRF) that act specifically in myeloid precursors. The cytolytic activity of GZB in target cells induces apoptosis by caspases or BID pathway.

Figure 5

The role of regulatory T cell (Treg) in maintaining the pathological condition. Treg can be stimulated by different mechanisms through the interaction with APC. When activated, Treg attenuates the harmful immunological responses usually associated with chronic inflammatory conditions, autoimmune diseases, and allergic processes of the mucosa, in order to maintain immune homeostasis and decreased tissue injury. In contrast, the maintenance of the immune response provides the persistence of infectious agents and favors the establishment of microenvironments that are conducive to tumor metastasis (TCD8⁺, cytotoxic T lymphocytes; TCD4⁺, helper T lymphocytes; APC, antigen-presenting cells; TH2, T helper type 2 lymphocytes; LB, B lymphocytes; PL, plasmocytes).