Plasticity of CD4+ FoxP3+ T cells
Introduction
The immune system is designed to recognize and destroy foreign pathogens while preserving immune tolerance to self. Mechanisms of self-tolerance in the periphery are essential to control rare thymocytes with self-reactivity that escape central tolerance because of a lower threshold of affinity for self-peptide or the lack of thymic expression of tissue-specific proteins. In recent years, we have learned that suppressor, or so-called ‘regulatory T cells (Tregs)’ play a prominent role in controlling peripheral autoreactive T lymphocytes. While the spectrum of regulatory/suppressor T cells includes multiple different T cell subsets; in this review, we will focus on FoxP3+ Tregs. Direct evidence for the essential role of FoxP3 comes from the observation that germline FoxP3 point mutations result in a lack of suppressive Tregs and fatal multiorgan autoimmune disease, termed scurfy disease in mice and Immunodysregulation Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome in humans [1, 2]. By comparison, ectopic FoxP3 expression in CD4+ non-Treg cells is sufficient to confer suppressor function in vitro and in vivo [3, 4, 5].
FoxP3+ Tregs have the capacity to actively block immune responses, inflammation, and tissue destruction by suppressing the functions of an array of cell types including conventional CD4+ helper T cells, B cell antibody production and affinity maturation, CD8+ cytotoxic T lymphocyte activity, and antigen-presenting cell function and maturation state. There are more than 15 different mechanisms of suppressor function that have been attributed to Tregs [6] which play a key role in regulating immune responses as a global ‘brake’ on immunity. However, it has become increasingly clear that CD4+ T cell subsets are not stable, and display plasticity during development/differentiation and maintenance.
Section snippets
FoxP3 expression and Tregs
Fate decisions for FoxP3 expression and thymically derived natural (n)Treg function are determined early in thymocyte development [7] with nTregs developing from FoxP3−, CD4+CD8−CD25+ mature thymocytes [8]. Using an elegant technique of cloning TCRs from nTregs, and retrovirally transduced conventional T cells, Hsieh et al. [9] reported that the peripheral Treg pool is skewed toward a self-reactive repertoire requiring that anergy and other Treg transcriptional programs restrain nTregs from
Treg stability/instability
The majority of nTregs are relatively stable in the healthy immune system. Floess et al. and Gavin et al. showed that most Tregs retain high FoxP3 expression following adoptive transfer in a nonpathogenic setting [15•, 16••]. However, 10–15% of ‘stable’ Treg cells were found to lose FoxP3 expression after adoptive transfer into lymphopenic hosts [16••]. There are two fates for Tregs that lose FoxP3 in lymphopenic hosts: death or dedifferentiation. A recent study showed that half of the Tregs
What are the consequences of the loss of FoxP3 expression and Treg stability?
Early reports suggested that the loss of FoxP3 and its associated phenotypic signature would lead to increased Treg cell death and the loss of FoxP3-expressing Tregs. Unless there was a catastrophic loss of the regulatory T cell subset, the limited Treg-deficiency would have minimal impact because of the stable FoxP3+ Tregs still remaining. However, there is increasing evidence that the FoxP3-deficient ‘exTregs’ survive in multiple settings and may have an important biologic function
Conclusions
Increasing evidence suggests that Tregs might be a dynamic population that under certain conditions can become unstable. A better understanding of the extracellular and intracellular signals that maintain or destabilize FoxP3 may have important therapeutic applications in a variety of disease settings ranging from autoimmunity to cancer and infectious disease.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The authors thank the members of the Bluestone laboratory for the many experiments that represent the basis for this review. This research was supported by grants from the JDRF, NIAID, and NIDDK. LTJ was supported by a fellowship from the Swiss National Science Foundation, the Roche Research Foundation and the Novartis Foundation formerly Ciba-Geigy Jubilee Foundation.
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These individuals have contributed equally to the studies and manuscript preparation.