Foxp3 and dominant tolerance

The hallmark of the adaptive immune system is the random generation of antigen receptors in developing lymphocyte clones through a process of somatic cell gene rearrangement mediated by the recombination-activating gene recombinase. The essentially unlimited specificities of this anticipatory recognition system provide an efficient counterbalance to the short reproduction cycles and high mutation rates of infectious micro-organisms. However, the diversity of antigen recognition afforded by the system also poses the threat of autoimmunity due to the generation of self-reactive receptors.

T cell receptors (TCR) recognize short peptides derived from foreign and self antigens bound to products of highly polymorphic major histocompatibility gene complex (MHC). MHC molecules sample peptide products of constitutive protein breakdown. CD4 T cells, a major subset of T cells playing a commanding role in regulation of both adaptive and innate immune system, recognize MHC class II molecules bound to peptides generated in the endocytic compartment of antigen-presenting cells (APCs) in the process of degradation of foreign and self-protein antigens. The majority of MHC-bound peptides presented on the surface of APCs are derived from self-proteins, and these complexes are involved in shaping T cell repertoire in the thymus and the periphery. TCR generated in the thymus are subjected to a stringent selection process. Thymocytes expressing TCR with a certain low affinity for self-peptides bound to MHC molecules displayed on thymic cortical epithelial cells undergo further maturation or positive selection. In contrast, thymocytes with a high affinity for self peptide–MHC complexes are subjected to negative selection resulting from apoptosis or functional inactivation. However, the latter process, collectively recognized as recessive tolerance, is not 100% efficient and autoreactive T cells are normally found within mature peripheral T cell subsets. A unique mechanism dubbed ‘dominant tolerance’ has been proposed to counter this threat. Dominant tolerance involves regulation of exuberant reactivity of lymphocytes against self and environmental antigens by a specialized population of regulatory T cells (T_R) acting in a dominant suppressive fashion.

Efforts to better define the cell type mediating suppression of autoimmunity culminated in the identification of CD4 T cells constitutively expressing the interleukin 2 receptor (IL-2R) α-chain (CD25) as being highly ‘enriched’ in suppressor activity. These ‘naturally arising’ CD4⁺CD25⁺ T_R became the best candidates for the cell population mediating dominant tolerance to self. However, IL-2R is not a unique marker of T_R cells, as all activated T cells transiently express CD25. A search for a specific molecular marker for T_R guided major research efforts, leading to discovery of specific genetic mechanisms governing their development and function.

In the course of these studies in mice the transcription factor Foxp3 was identified as a definitive molecular T_R cell marker by my own group and two other laboratories (Fontenot et al. 2003; Hori et al. 2003; Khattri et al. 2003). Several years ago, mutations in the X-chromosome-encoded Foxp3 gene were identified as the cause of the early-onset fatal autoimmune disorder observed in humans with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX patients) and in a mutant mouse strain scurfy that spontaneously develop autoimmune disease (Chatila et al. 2000; Bennett et al. 2001; Brunkow et al. 2001; Wildin et al. 2001). To understand a role of Foxp3 in T_R biology, mice harbouring conditional Foxp3 allele and targeted disruption of Foxp3 gene in the germ-line were generated. Examination of chimeric mice containing a mixture of Foxp3-deficient and wild-type haematopoietic precursor cells demonstrated that T_R cells fail to develop from Foxp3-deficient progenitors (Fontenot et al. 2003, 2005). As a corollary to these results, Sakaguchi and co-workers and our group found that retroviral Foxp3 gene transfer into peripheral non-T_R cells results in acquisition of suppressive function (Fontenot et al. 2003; Hori et al. 2003). Together, these studies reveal a principal role for Foxp3 in guiding T_R-cell development and function.

Analysis of Foxp3 expression using a reporter Foxp3 allele generated by ‘knocking-in’ green fluorescent protein (GFP) into the Foxp3 gene, illustrated in figure 1, suggests that Foxp3 is a T_R-cell-lineage specification factor uniquely expressed in a subset of peripheral and thymic T cells with potent suppressive activity (Fontenot et al. 2005). Thus, Foxp3 is a dedicated and highly specialized genetic mechanism for the generation of T cells that can promote dominant tolerance.

Figure 1.

T lymphocytes develop the regulatory phenotype of dominant tolerance due to their expression of the gene Foxp3. (a) Scanning electron micrograph of a T lymphocyte; (b) Foxp3-gfp gene construct (Fontenot et al. 2005) encoding both Foxp3 protein and green fluorescent protein; (c) introduction of the Foxp3-gfp gene construct into the mouse genome has enabled direct visualization of regulatory T lymphocytes within the thymus, revealed as individual fluorescent green cells alongside a blood vessel.

This issue contains a wide range of review articles building on the discovery of Foxp3's role in T_R biology and other recent advances in the field and covering various basic and clinical aspects of dominant tolerance.