Trends in Immunology
Volume 29, Issue 9, September 2008, Pages 429-435
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Review
Natural and TGF-β–induced Foxp3+CD4+ CD25+ regulatory T cells are not mirror images of each other

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Foxp3+ CD4+ CD25+ regulatory cell (Treg) subsets that maintain immunologic homeostasis have been considered to be a homogeneous population of naturally occurring, thymus-derived CD4+CD25+ cells (nTregs). However, similar Foxp3+ Tregs can be induced from CD25 precursors in vivo, and ex vivo with interleukin 2 (IL-2) and transforming growth factor β (TGF-β) (iTregs). These two subsets differ in their principal antigen specificities and in the T-cell receptor signal strength and co-stimulatory requirements needed for their generation. However, whether iTregs have any unique functions in vivo has been unclear. Although IL-6 can convert nTregs to Th17 cells, iTregs induced by IL-2 and TGF-β are resistant to this cytokine and thereby might retain suppressive function at inflammatory sites. Thus, nTregs and iTregs may have different roles in the adaptive immune response.

Introduction

Regulatory T cells (Tregs) control the reactivity of self-aggressive T cells not eliminated in the thymus and are responsible for keeping the immune system in homeostatic balance. Although Tregs consist of heterogeneous subsets that include CD4+ cells, CD8+ cells and natural killer (NK) T cells, those that express the Foxp3+ transcription factor are essential to maintain immunologic homeostasis [1]. These consist predominantly of CD4+ cells and can be divided into two principal subsets: naturally occurring, thymus-derived natural CD4+ cells that express CD25, the α chain of the interleukin 2 (IL-2) receptor (nTregs) 2, 3 and adaptive CD4+CD25+ cells that are induced from CD25- precursors in peripheral lymphoid organs (iTregs) [4]. Both nTregs and iTregs share a similar phenotype and have a contact-dependent mechanism of action that is poorly understood. nTregs express CTLA-4 (cytotoxic T lymphocyte antigen 4), GITR (gluccorticoid-induced tumor necrosis factor receptor), CCR4 (chemokine receptor) and CD62L, and most are previously activated cells (i.e. CD45RBlow in the mouse and CD45RO in the human). iTregs induced with IL-2 and transforming growth factor β (TGF-β) have a similar phenotype except that they are generated from naive CD4+ cells and require additional stimulation to develop memory markers. The few CD4+CD45RA+CD25+ cells in the naïve fraction, however, have the highest regenerative capacity [5] and can markedly enhance the numbers of CD4+CD25- cells that become CD25+ iTregs [6].

Both IL-2 and TGF-β have important, nonredundant effects on Foxp3+ nTregs and iTregs 7, 8, 9. Similarities include a crucial role of both of these cytokines in the maintenance and survival of both Treg cell subsets. There are important differences, however, in their antigen specificities, generation requirements and the stability of suppressive activity that raise the possibility that nTregs and iTregs have separate functions in the adaptive immune response. These topics and differences between mouse and human Foxp3+ Treg cells will be discussed in this article.

Section snippets

Differing T-cell receptor signal strength and co-stimulatory molecules for the generation of nTregs and iTregs

nTregs and iTregs differ in their principal antigen specificities and strength of T-cell receptor (TCR) stimulation needed for their generation (Table 1). nTregs primarily develop in response to self-antigens expressed in the thymus and iTregs by environmental antigens presented by dendritic cells (DCs) in peripheral lymphoid organs. Probably because they are derived from continuously proliferating precursor cells, nTregs generated in the thymus require high affinity interactions with cognate

Differences in IL-2 and TGF-β requirements for the generation of nTregs and iTregs

Mice with genetic deficiencies of TGF-β1, CTLA-4 and Foxp3 all develop a rapidly fatal autoimmune lymphoproliferative syndrome 24, 25, 26. IL-2–deficient mice also develop multiorgan autoimmune disease [27]. nTregs are present in the thymus of TGF-β– and IL-2–deficient mice, but peripheral CD25- cells from these mice need both of these cytokines to become Foxp3+ iTregs. As stated above, CTLA-4 is needed for TGF-β to induce Foxp3+ iTregs [15]. Therefore, in peripheral lymphoid organs, both IL-2

IL-2 and TGF-β are needed for the maintenance and survival of nTregs and iTregs

Although IL-2 and TGF-β are required only for the generation of iTregs, both of these cytokines are needed for the maintenance of Foxp3 expressed by nTregs and iTregs. Foxp3 expressed by peripheral but not thymic CD4+ cells from IL-2– or TGF-β–deficient mice is markedly decreased 9, 37. Foxp3 expression by nTregs, however, is more stable than iTreg cells, possibly because these cells are being continuously stimulated by self-antigens. Foxp3 expressed by mouse and human iTregs rapidly decays in

The role of TGF-β and other molecules in the functional activities of nTregs and iTregs

There is now a large body of evidence that supports a major role for TGF-β in the mechanism of action of both nTregs and iTregs. The first demonstration of TGF-β–dependent iTregs was in 1993 where a study to determine how oral tolerance prevents experimental allergic encephalomyelitis revealed CD8+ suppressor cells that secreted TGF-β [42]. Other diseases where protective TGF-β–producing iTregs have been described more recently include autoimmune diabetes, inflammatory bowel disease and

IL-6 alters the stability of mouse Foxp3+ nTreg but not iTreg cells

A surprising recent finding is that the combination of IL-6 and TGF-β can induce mouse T cells to become IL-17 producing (Th17) 61, 62. IL-23 produced by immunogenic DCs completes the differentiation of these T cells into proinflammatory Th17 cells. These proinflammatory cells seem to play an important role in the control of certain bacterial infections by mechanisms that include the recruitment of neutrophils. TGF-β can upregulate expression of RORγt, a transcription factor needed for IL-17

Concluding remarks

We have reviewed the crucial role of IL-2 and TGF-β in the generation of iTregs and in the maintenance and stability of both nTregs and iTregs. These two subsets differ in their mechanisms of generation and in the effect of IL-6 on their functional properties. However, the IL-6 difference seems to reflect the previous exposure of iTregs to IL-2 and TGF-β rather than because of lineage differences. These findings emphasize the importance of normal IL-2 production to prevent autoimmunity.

Acknowledgements

We are indebted to all the members of our laboratory for their contribution to our investigations and acknowledge grants from the National Institutes of Health, the George and Mary Treadwell Foundation, the Arthritis Foundation, the Arthritis National Foundation and ExCell Therapeutics. D.A.H. is a consultant for Becton Dickenson Biosciences

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