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(Journal of Leukocyte Biology. 2003;74:961-965.)
© 2003 by Society for Leukocyte Biology

The main function of IL-2 is to promote the development of T regulatory cells

Department of Microbiology and Immunology, University of Miami School of Medicine, Florida

¹ Correspondence: Department of Microbiology and Immunology, University of Miami School of Medicine, 1638 N.W. 10th Avenue, Room 718A, McKnight Building, Miami, FL 33136. E-mail: tmalek{at}med.miami.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION IL-2 PROVIDES AN ESSENTIAL... IL-2 IS ESSENTIAL FOR... IL-2 DRIVES THE EXPANSION... ADOPTIVE TRANSFER OF T... REVISED PARADIGM FOR THE... REFERENCES

 
Based primarily on vitro studies, interleukin (IL)-2 has been considered a key growth and death factor for antigen-activated T lymphocytes. IL-2 is also essential to maintain self-tolerance, as IL-2- and IL-2 receptor-deficient mice exhibit lethal autoimmunity. The intrinsic death-sensitizing activity of IL-2 was thought to be a key mediator for apoptosis of peripheral autoreactive T cells. However, recent in vivo studies strongly favor a model whereby IL-2 controls autoimmunity through the production of CD4⁺CD25⁺ T regulatory (Treg) cells. In this setting, IL-2 is essential for expansion of Treg cells within the thymus and in peripheral neonatal-immune tissue. Thus, from being considered the primary growth factor for antigen-activated T lymphocytes, these new findings redefine the pivotal role for IL-2 as the major inducer for the developmental production of suppressive Treg cells.

Key Words: CD4⁺CD25⁺ • autoimmunity • IL-2

	INTRODUCTION

TOP ABSTRACT INTRODUCTION IL-2 PROVIDES AN ESSENTIAL... IL-2 IS ESSENTIAL FOR... IL-2 DRIVES THE EXPANSION... ADOPTIVE TRANSFER OF T... REVISED PARADIGM FOR THE... REFERENCES

 
Interleukin (IL)-2 is a small (15-kDa) -helical cytokine produced primarily by recently activated T cells, which induce its biological response after binding to a high-affinity receptor. The IL-2 receptor (IL-2R) is comprised of three subunits, an -chain that functions only for IL-2 binding, and the ß and subunits, which function to augment ligand binding and induce cellular signaling. The textbook view of IL-2 still remains that it is the most critical cytokine for promoting the clonal expansion of recently antigen-activated T cells. Numerous papers extol the growth factor activity of IL-2, which facilitates studies of T cell specificity and function in vitro and permits the generation of large numbers of nontransformed antigen-specific T cells for molecular analysis or therapeutic purposes. Furthermore, the perceived importance of IL-2 in promoting immune responses has made this cytokine and its receptor a prime target to suppress unwanted immune responses, such as those that occur in autoimmune disease or transplant rejection reactions.

When the genes for IL-2, IL-2R, or IL-2Rß were inactivated in mice by gene targeting, an unexpected and counter-intuitive result occurred. In each case, the knockout mice died early in life, typically at 4–12 weeks, of a massive lymphoproliferative syndrome accompanied by severe autoimmunity [^{1 2 3} ]. Although this result did not alter the view that IL-2 was a key T cell growth factor, models were revised that emphasized another property of IL-2. Antigen-activated T cells expand in response to IL-2 and become very sensitive to apoptosis if restimulated by antigens through their T cell receptor (TCR) [⁴ , ⁵ ]. This phenomenon was coined as activation-induced cell death (AICD) and was proposed as a key missing-element leading to lymphoproliferation and autoimmunity in IL-2/IL-2R-deficient mice. The failure of the death-sensitizing activity of IL-2 was thought to allow autoreactive T cells, which escape thymic-negative selection, to proliferate unchecked to autoantigens in the periphery. This hypothesis gained popularity when it was shown that AICD was dependent on Fas and Fas-L [^{6 7 8} ], as mice deficient in either of these two genes also exhibit lymphoproliferation and autoimmune disease. However, it is noteworthy that the nature and time course of lethal disease in IL-2/IL-2R- versus Fas/FasL-deficient mice differ, indicating that a defect in Fas-dependent apoptosis is not the essential link for autoimmunity associated with IL-2 deficiency. More importantly, there still remain no direct in vivo data to confirm the AICD hypothesis for autoimmunity in IL-2/IL-2R-deficient mice.

	IL-2 PROVIDES AN ESSENTIAL SIGNAL DURING THYMIC DEVELOPMENT

TOP ABSTRACT INTRODUCTION IL-2 PROVIDES AN ESSENTIAL... IL-2 IS ESSENTIAL FOR... IL-2 DRIVES THE EXPANSION... ADOPTIVE TRANSFER OF T... REVISED PARADIGM FOR THE... REFERENCES

 
At one time, it was thought that IL-2 functioned within the thymus, primarily based on the expression of CD25 on a subset of "double negative" pro/pre-T cells and the capacity of anti-CD25 monoclonal antibodies to affect thymic development [^{9 10 11} ]. However, this hypothesis was dismissed, as thymic development was largely normal in IL-2^-/- mice early in life before the severe pathology of autoimmunity became apparent [¹² ]. Here, "normal" was initially assayed with respect to cellularity and distribution of CD4 and CD8 thymic subsets. Later, others showed that negative selection, especially for CD8-lineage cells, was also normal [¹³ , ¹⁴ ].

Based on the prevailing view that IL-2 is a critical T cell growth and death factor for peripheral T lymphocytes, it was unexpected when we found that expression of IL-2Rß in the thymus of IL-2Rß^-/- mice prevented lethal autoimmunity and extreme T cell lymphoproliferation [¹⁵ ]. This finding strongly suggested that the key function of IL-2Rß lies within the thymus rather than peripheral lymphoid tissue. Although IL-2Rß is a subunit of the IL-2R and the IL-15R, the prevention of autoimmunity is attributed to IL-2, as autoimmunity is associated with IL-2 but not IL-15 deficiency. Thus, IL-2 appears to function critically during thymic development.

Thymic-specific expression of IL-2Rß in IL-2Rß^-/- mice did not simply delay the onset or severity of autoimmune disease but actually cured the mice of the lethal lymphoproliferative and autoimmune disorder. These transgenic mice were fertile and lived a normal lifespan. When compared with normal C57BL/6 mice, the cellularity of the spleen and lymph nodes was sometimes increased (25–50%), primarily as a result of an increased fraction of CD4⁺ T cells. Nevertheless, this change in cellularity was still skewed far toward normal, as the peripheral cellularity, particularly of lymph nodes of IL-2Rß^-/- mice, is typically increased five- to tenfold, and a high proportion of T cells express an activated phenotype. It is important that the T cells in these transgenic mice did not exhibit an activated cell-surface phenotype when enumerating the fraction of CD69⁺, CD62L^low, or CD44^high cells. Furthermore, autoimmune pathology, i.e., multiorgan inflammatory responses and autoantibodies, was always observed in IL-2Rß^-/- mice, whereas this was rarely seen in IL-2Rß^-/- mice that expressed thymic IL-2Rß.

Extensive in vitro studies confirmed that T cells from these transgenic IL-2Rß^-/- mice were extremely nonresponsive to IL-2 in various proliferative and functional assays, including development of cytolytic T lymphocytes and interferon--secreting effector cells [¹⁵ , ¹⁶ ]. Thus, consistent with much-published data, T cells from IL-2Rß-transgenic IL-2Rß^-/- mice showed an essential role for IL-2R signaling for extensive T cell proliferation and effector cell development in vitro. It is interesting that T cell immunity in these mice is not severely impaired, as they readily mounted antibody responses to nominal antigen, CD8 T cell responses to virus, and primary and secondary allogeneic skin graft rejection reactions [¹⁷ ]. Nevertheless, after in vivo activation, T cells from the IL-2Rß-transgenic IL-2Rß^-/- mice were similarly nonresponsive to IL-2 and IL-15 in proliferative assays. These data illustrate a critical dichotomy for T cell-dependent immune responses; IL-2 is essential in vitro but is not mandatory in vivo. Importantly, as these transgenic IL-2Rß^-/- mice are autoimmune-free and do not exhibit a lymphoproliferative disorder, we concluded from all these results that the function of IL-2Rß related to controlling self-reactivity is dissociated from that regulating peripheral T cell immunity and is not a result of an intrinsic defect in peripheral T cells.

	IL-2 IS ESSENTIAL FOR THE PRODUCTION OF CD4+CD25+ T REGULATORY (TREG) CELLS

TOP ABSTRACT INTRODUCTION IL-2 PROVIDES AN ESSENTIAL... IL-2 IS ESSENTIAL FOR... IL-2 DRIVES THE EXPANSION... ADOPTIVE TRANSFER OF T... REVISED PARADIGM FOR THE... REFERENCES

 
If the main nonredundant function of IL-2 lies at the level of the thymus, the most important question was to establish the role for the thymic IL-2/IL-2R interaction. Two major hypotheses were considered. The first was that IL-2 contributes to thymic negative selection, perhaps through an AICD mechanism, as proposed for peripheral T cells. To test this idea, IL-2Rß deficiency was bred onto the BALB/c and DBA/2 genetic backgrounds, as these two strains readily undergo endogenous, superantigen-mediated, thymic negative selection [¹⁸ ]. Both of these strains exhibit a severe form of lethal autoimmunity, even more severe than seen with C57BL/6 IL-2Rß^-/- mice. With just one exception—Vß12 on CD4 T cells in BALB/c mice—deletion of all other Vßs for CD4 and CD8 T cells in DBA/2 and BALB/c IL-2Rß^-/- mice was normal, strongly suggesting that IL-2 function was not required for thymic negative selection.

The other hypothesis we explored was that IL-2 was required for the production or function of CD4⁺CD25⁺ Treg cells. These cells are derived during thymic development and primarily function to suppress peripheral autoreactive CD4⁺ T cells that escape thymic negative selection [¹⁹ , ²⁰ ]. Several observations by other laboratories lend some credence to this idea. First, autoimmunity in IL-2Rß^-/- mice was shown to be a result of autoreactive CD4⁺ T cells [²¹ ]. Second, the periphery of IL-2^-/- mice was reported to contain a reduced proportion of CD4⁺CD25⁺ T cells [²² ]. Lastly, adoptive transfer of normal bone marrow or T cells prevented some of the abnormal activities associated with IL-2- or IL-2Rß-deficient T cells [^{23 24 25} ]. These latter studies were important, as they also indicated that the problems in IL-2^-/- and IL-2Rß^-/- mice were not the result of an intrinsic T cell defect.

When compared with normal mice, IL-2Rß^-/- mice had a significantly reduced population of CD4⁺CD25⁺ thymocytes and essentially lacked these cells in the peripheral lymphoid compartment [¹⁸ ]. Thus, although a few Treg cells arise in the absence of IL-2 signaling during thymic development, their subsequent survival or expansion appears to be impaired. It is important that CD4⁺CD25⁺ T cells were restored in the thymus and the periphery in IL-2Rß-transgenic IL-2Rß^-/- mice. In fact, these transgenic IL-2Rß^-/- mice typically contained an increased number of these cells when compared with normal mice. The precise reason for this in not known. This reconstituted population was indeed Treg cells, as they exhibited potent, suppressive activity when tested ex vivo by inhibiting anti-CD3-induced proliferation of conventional CD4⁺ T lymphocytes.

The above result simply correlated expression of the IL-2Rß transgene with production of CD4⁺CD25⁺ Treg cells. To directly investigate the inter-relationship between Treg activity, IL-2Rß function, and autoimmunity, we tested whether adoptive transfer of Treg cells into IL-2Rß^-/- mice affected the onset of the inevitable lethal autoimmunity. As the first week of life is a key period for the production of Treg cells [¹⁹ , ²⁰ ], purified CD4⁺CD25⁺ T cells were adoptively transferred into unmanipulated IL-2Rß^-/- mice during the first 24–48 h after birth. In virtually every case, a single injection of 0.3–1 x 10⁵ CD4⁺CD25⁺ splenic T cells from normal syngeneic mice was sufficient, not just to inhibit but to actually prevent lethal autoimmunity in BALB/c IL-2Rß^-/- mice [¹⁸ ]. More recent experiments indicate that 1–2 x 10⁵ Treg cells similarly prevented autoimmunity in C57BL/6 IL-2Rß^-/- mice. Furthermore, the engrafted, donor-derived CD4⁺CD25⁺ T cells were shown to express Treg activity when assayed in vitro. Quite remarkably, the phenotype of these adoptively transferred IL-2Rß^-/- mice closely paralleled that observed for the IL-2Rß-transgenic IL-2Rß^-/- mice. Thus, the properties of these two distinctive mouse models provide the foundation for the conclusion that the main nonredundant role of IL-2 and IL-2R is the production of Treg cells.

	IL-2 DRIVES THE EXPANSION OF CD4+CD25+ TREG CELLS

TOP ABSTRACT INTRODUCTION IL-2 PROVIDES AN ESSENTIAL... IL-2 IS ESSENTIAL FOR... IL-2 DRIVES THE EXPANSION... ADOPTIVE TRANSFER OF T... REVISED PARADIGM FOR THE... REFERENCES

 
Transferring allotype-marked (CD45.1) donor cells into congenic CD45.2 C57BL/6 IL-2Rß^-/- recipient mice made two interesting observations [¹⁸ ]. First, even a minor contamination of CD8⁺ T cells resulted in significant engraftment of donor CD8⁺ T cells, which expressed a memory-like phenotype. However, CD8⁺ T cells do not contribute to suppressing autoimmunity in IL-2Rß^-/- mice, as a similar, low number of rigorously purified CD4⁺CD25⁺ T cells prevented autoimmunity without significant CD8 donor engraftment [¹⁸ ], and the transfer of purified CD8⁺ T cells did not affect the onset or severity of disease in the IL-2Rß^-/- recipient animals (unpublished). In this latter case, a massive expansion of the CD8⁺ donor T cells was observed in the absence of Treg cells, which is likely the net result of IL-15-driven homeostatic proliferation of these cells in IL-2Rß^-/- mice and the absence of Treg cells that control such homeostatic proliferation [²⁶ ].

The second observation, which is more important with respect to Treg function, is that there was a large expansion of donor-derived CD4⁺CD25⁺ Treg cells. Just by enumerating the number of donor-derived CD4⁺CD25⁺ T cells in the peripheral-immune compartment in recipient IL-2Rß^-/- mice, without taking into consideration the inefficiency in engraftment, we calculated a minimum of a 15- to 20-fold expansion of Treg cells during the first 4–8 weeks after adoptive transfer. As these mice did not exhibit any signs of autoimmunity, this expansion is unlikely a result of a cytokine-rich environment as a consequence of self-reactivity. This observation and those of Annacker et al. [²⁷ ], which followed the fate of carboxyfluorescein diacetate succinimidyl ester (CSFE)-labeled Treg cells in vivo, demonstrate substantial proliferative potential of Treg cells in vivo and call into question the notion that Treg cells are "anergic suppressor cells," a term coined for Treg cells based on their poor growth properties in vitro.

Does this large expansion of donor-derived CD4⁺CD25⁺ Treg cells require IL-2? Similar attempts to prevent autoimmunity by transferring wild-type Treg cells into IL-2-deficient mice were unsuccessful and not accompanied by donor cell engraftment [¹⁸ ]. Furthermore, unlike wild-type CD4⁺CD25⁺ Treg cells, which express all subunits required for a functional, high-affinity IL-2R [¹⁸ ], the CD4⁺CD25⁺ in IL-2Rß-transgenic IL-2Rß^-/- mice expressed normal levels of CD25 (IL-2R) and c but undetectable levels of IL-2Rß. The adoptive transfer of these IL-2R-defective Treg cells into IL-2Rß^-/- mice also failed to prevent autoimmune disease. Furthermore, two other recent studies have directly implicated IL-2 in the production of Treg cells. In both cases, recipient-derived IL-2 supported the expansion and autoimmune-suppressive activity of CD4⁺ Treg cells, which were derived from IL-2^-/- mice. Furtado et al. [²⁸ ] showed that a small number of CD4⁺ T cells from IL-2^-/- but not CD25^-/- mice were effective in protecting mice from spontaneous autoimmune encephalomyelitis. In a chimeric adoptive-transfer setting, Almeida et al. [²⁵ ] showed that normal Treg cells or IL-2^-/- precursor cells prevented the large accumulation of activated T cells derived from CD25^-/- mice. Thus, cells within recipient autoimmune-prone mice must produce IL-2, and Treg cells must express a functional, high-affinity IL-2R for their expansion and capacity to prevent self-reactivity. As will be discuss more fully below, the maintenance of CD4⁺CD25⁺ Treg cells, which do not express IL-2Rß in the periphery of adult IL-2Rß-transgenic IL-2Rß^-/- mice, raises interesting questions concerning the role of IL-2 for the homeostasis of these cells.

	ADOPTIVE TRANSFER OF T CELLS INTO IL-2R-/- MICE: A MODEL TO SPECIFICALLY STUDY TREG CELLS IN VIVO

TOP ABSTRACT INTRODUCTION IL-2 PROVIDES AN ESSENTIAL... IL-2 IS ESSENTIAL FOR... IL-2 DRIVES THE EXPANSION... ADOPTIVE TRANSFER OF T... REVISED PARADIGM FOR THE... REFERENCES

 
Coexpression of CD4 and CD25 by T cells is not only a phenotype for Treg cells, but the display of these surface markers is also a characteristic for conventional, activated T cells after antigen encounter. Therefore, one major difficulty in many studies that investigate CD4⁺CD25⁺ Treg cells, especially in the peripheral-immune compartment, is that defining properties of CD4⁺CD25⁺ T cells is not necessarily equivalent to defining properties of Treg cells. However, when CD4⁺CD25⁺ T cells are adoptively transferred into IL-2Rß^-/- mice, the presence of donor CD4⁺CD25⁺ T cells represents a situation where virtually all the CD4⁺CD25⁺ T cells are Treg cells.

Three lines of evidence support this conclusion [¹⁸ ]. First, adoptive transfer leads to stable engraftment of donor CD4⁺CD25⁺ T cells in IL-2Rß^-/-mice but not in control normal mice. Second, only CD4⁺CD25⁺ donor T cells prevented autoimmunity in IL-2Rß^-/- mice, and these donor T cells were anergic and suppressive in vitro. Third, 95% of the donor T cells were CD4⁺CD25⁺, and there were very few (1–3%) CD4⁺ recipient T cells that expressed CD25. This skewing in the relative abundance of CD4⁺CD25⁺ T cells cannot simply be explained by a defect in CD25 expression or responsiveness by recipient IL-2Rß^-/- T cells, as in the absence of autoimmunity, IL-2Rß nonresponsive, peripheral CD4⁺ T cells expressed CD25 after TCR stimulation and readily participated in T cell-dependent, immune responses in vivo [¹⁶ , ¹⁷ ]. In other words, if a substantial fraction of the engrafted donor CD4⁺CD25⁺ T cells in IL-2Rß^-/- mice actually represented recently antigen-activated, conventional T lymphocytes, recipient CD4⁺CD25⁺ T cells are expected to be equivalently prevalent. Collectively, these observations indicate that donor-derived CD4⁺CD25⁺ T cells selectively fill a cellular niche or lineage that was absent in IL-2Rß^-/- mice and are primarily Treg cells. Therefore, further characterization of donor CD4⁺CD25⁺ T cells in adoptively transferred IL-2Rß^-/- mice represents a model system for defining in vivo properties of CD4⁺CD25⁺ Treg cells without complications from conventional antigen-activated T lymphocytes. Our laboratory is currently using this model to define the growth, homeostasis, and specificity of Treg cells.

	REVISED PARADIGM FOR THE IN VIVO NONREDUNDANT FUNCTION OF IL-2

TOP ABSTRACT INTRODUCTION IL-2 PROVIDES AN ESSENTIAL... IL-2 IS ESSENTIAL FOR... IL-2 DRIVES THE EXPANSION... ADOPTIVE TRANSFER OF T... REVISED PARADIGM FOR THE... REFERENCES

 
Our current view is that the essential, nonredundant function of the IL-2/IL-2R interaction encompasses its role in the production of CD4⁺CD25⁺ Treg cells. There appear to be two levels where IL-2 exerts this effect (Fig. 1 ). The first is within the thymus and is exemplified by the capacity of thymic expression of IL-2Rß to increase the numbers of Treg cells in the thymus of IL-2Rß^-/- mice. The second is within the periphery of neonatal mice, as there was substantial expansion of normal Treg cells upon adoptive transfer into neonatal IL-2Rß^-/- mice. As Treg cells did not engraft the thymus, even very early (several days) after adoptive transfer (Allison Bayer and T. R. Malek, unpublished), it is highly likely that the large expansion of donor Treg cells occurs in the periphery. Thus, IL-2 appears to function as an essential developmental cytokine for Treg cells. One very simple view is that IL-2 is a T cell growth factor for Treg cells. However, IL-2 might also provide survival and differentiation signals. Our current work is aimed at investigating these issues.

View larger version (19K): [in this window] [in a new window]   Figure 1. Model for IL-2 in the production and homeostasis of CD4+CD25+ Treg cells. (A) A few Treg cells arise within the thymus, possibly through selection on self-autoantigens, and undergo an initial IL-2-dependent expansion. (B) After export to the periphery early in life, the development of Treg cells continues, leading to a further IL-2-dependent increase in Treg cell number. (C) After this developmental production and expansion, Treg cell homeostasis in peripheral-immune tissues of an adult occurs without a strict requirement for IL-2. It remains to be determined the extent by which IL-2 contributes to Treg cell homeostasis.

	ACKNOWLEDGEMENTS

 
My research is supported by the National Institutes of Health (R01-AI40114-01; R01-CA45947). I thank Allison Bayer for critically reading this manuscript.

Received June 13, 2003; accepted July 18, 2003.

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TOP ABSTRACT INTRODUCTION IL-2 PROVIDES AN ESSENTIAL... IL-2 IS ESSENTIAL FOR... IL-2 DRIVES THE EXPANSION... ADOPTIVE TRANSFER OF T... REVISED PARADIGM FOR THE... REFERENCES

 

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