The Paradox of Foreign Antigen Recognition by Regulatory T Cells

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The above description of self-reactivity within the naturally arising regulatory T cell population fits with the original identification of regulatory T cells as a critical mechanism for the prevention of autoimmunity. However, it has become increasingly evident that TR play an important role in the regulation ofvirtually all immune responses. While initial studies focused on defining the progression of a variety of autoimmune responses in the absence or presence of regulatory T cells, more recent studies have examined the role of TR in the regulation of immune responses to foreign antigens.

For example, it has been reported that infection of mice with Helicobacter hepaticus results in the generation of both CD25+ and CD25- cells capable of producing IL-10 in response to bacterial antigens and suppressing Helicobac-ter-induced inflammatory colitis (Kullberg et al. 2002). As in aforementioned studies, it is not clear whether these IL-10-producing T cells originate from naturally arising CD25+ TR or differentiate from the CD25- T cell population. As Helicobacter is considered to be a commensal microorganism in immunocompetent hosts, it is intriguing to hypothesize that gut flora may significantly influence the TCR repertoire of "naturally arising" CD25+ T cell populations (as well as CD25- populations) by facilitating selective expansion of TR and CD25- T cell clones bearing TCR reactive to bacterial antigens. Along the same line, studies of oral tolerance to foreign antigens have demonstrated the ability to generate CD25+ T cells with regulatory properties from CD25-T cells (Thorstenson and Khoruts 2001).

Thus, a portion of the normal naturally arising regulatory CD25+ T cell population in the periphery may actually contain adaptive CD25+ T cells produced upon interactions with foreign antigens. In support of this hypothesis, several groups have reported in vitro generation of CD25+ T cells with regulatory properties from peripheral CD25- T cells in both human and murine models (Chen et al. 2003; Nagler-Anderson et al. 2004; Walker et al. 2003b). In the latter, TGF-3 was shown to play an essential role in the "peripheral conversion" of murine CD25- T cells into CD25+ T cells with regulatory properties (Chen et al. 2003). Furthermore, von Boehmer's group has also reported on the generation of CD25+ TR from peripheral CD25- TCR transgenic x RAG-deficient T cells upon chronic provision of constant levels of the cognate peptide antigen using an osmotic peptide pump as a delivery device (Apos-tolou and von Boehmer 2004). Thus, these studies serve as a proof of principle that under certain circumstances, such as high levels of TGF-3, CD25+ regulatory T cells can arise from peripheral CD25- T cells upon encounter with their cognate antigen.

To complicate matters further, recognition of foreign antigen by the naturally arising CD25+ T cell population has also been demonstrated using immunization with hapten 2,4-dinitrofluorobenzene, or infection with Candida albicans or Leishmania major (Belkaid et al. 2002; Dubois et al. 2003; Montagnoli et al. 2002). For example, adoptive transfer studies revealed that the Leishmania-reactive CD25+ T cells accumulating at the sites of infection were derived primarily from the naturally arising CD25+, and not CD25-, donor T cells. In fact, it was observed that persistent immunologic memory to Leishmania as well as Candida requires the presence of these adaptive TR

originating from the naturally arising TR population, arguing for an important biological role for regulatory T cells in the down-modulation of immune responses to pathogens.

These reports describing reactivity to foreign antigens within the naturally arising TR population appear to be at odds with the prevalent paradigm of Tr development commencing upon recognition of high-affinity self-antigens in the thymus. One scenario that might account for both self- and foreign-antigen reactivity of TR would be that the TCR specificity requirements for TR

Thymus

Periphery

Mature

Precursor CD4+ thymocytes

Maintenance or

Maintenance/expansion / rn?c+ dependent on '

self-antigen encounter

Peripheral conversion > ( qq25+ due to encounter with

Peripheral conversion > { CD25+ upon recognition of foreign antigen

Fig. 2 Development of CD25+ regulatory T cells. Potential TCR-ligand interactions that may result in generation of CD25+ T cells with regulatory properties in the thymus (left) and in the periphery (right)

Maintenance or expansion due to self-antigen recognition expansion due to self-antigen recognition

Maintenance/expansion / rn?c+ dependent on '

self-antigen encounter

Peripheral conversion > ( qq25+ due to encounter with peripheral self-antigen peripheral self-antigen

Peripheral conversion > { CD25+ upon recognition of foreign antigen

CD25- regulatory cells specific for foreign antigen

CD25- regulatory cells specific for foreign antigen

Conventional CD25-T cell specific for foreign antigen

Fig. 2 Development of CD25+ regulatory T cells. Potential TCR-ligand interactions that may result in generation of CD25+ T cells with regulatory properties in the thymus (left) and in the periphery (right)

development is analogous to conventional CD25- T cell development, except that Tr are simply positively selectedbased on higher-avidity interactions with self-peptide:MHC class II complexes. A logical extension of this hypothesis is that the TR TCR repertoire may be functionally as diverse as the CD25-TCR repertoire, allowing for recognition of a wide variety of foreign antigens. The available evidence regarding the diversity of the TR TCR repertoire does not exclude such a possibility, as it has been shown that Va and Vp usage is similar between CD25+ and CD25- CD4+ T cells (Takahashi et al. 1998). The actual diversity of the TR TCR repertoire, however, has not been extensively studied until now (see below).

The possibility of a foreign antigen inducing peripheral conversion of CD25- T cells into CD25+ regulatory T cells as well as stimulating the expansion of naturally arising CD25+ T cells may significantly complicate our view of the development and function of naturally arising TR (Fig. 2). Thus, it is plausible that there may be several subsets within the peripheral TR population in regards to specificity of their TCR and their origin. Some peripheral Tr may develop in the thymus as a result of increased avidity recognition of self-antigen, whereas others may have been elicited from CD25- T cells under special conditions, e.g., upon chronic exposure to a foreign or self-antigen in the presence of TGF-p. Finally, thymically derived TR expanded upon encounter with a high-affinity foreign or self-antigen might also be found within the naturally arising TR population. The relative size of each of these putative subsets and their functional potential are, however, unknown.

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