Murine CD8+ regulatory T lymphocytes: The new era
Introduction
Regulation of immune responses by T lymphocytes has been a central tenet in immunology ever since the 1960s. The first era of so-called suppressor T cells rose with the original reports by Gershon and Kondo and by McCullagh in the early 1970s [1], [2], [3], and its demise seriously started only hardly more than a decade later most notably with the molecular characterization of the I–J locus. Genetic analyses suggested that I–J encoded a suppressor factor, but its molecular analysis showed that it did not encode any identifiable gene or transcript [4], [5]. This era in the history of immunology must have been intellectually very stimulating and still elicits strong viewpoints from historical authors [6], [7], [8], [9]. However, the demise of the field was in part caused by lack of tools and, as a consequence, inability to “distinguish poorly executed science from good science,” and “a significant level of indiscipline and poor training” [9]. Despite the observation that the historical suppressor T cells expressed CD8 (Ly2, Ly3) [10], [11], we therefore feel that we should focus this review on CD8+ ‘regulatory’ (rather than ‘suppressor’) T cells on data from the postsuppressor era.
During development of T lymphocytes in primary lymphoid organs, the genes encoding their antigen receptors undergo random somatic rearrangements. The resulting, still immature repertoire is therefore very large and contains many cells specific for self-antigens. Probably the majority of these potentially self-reactive cells are negatively selected by induction of anergy or apoptosis [12], [13]. However a significant number of potentially self-reactive lymphocytes leave the primary lymphoid organs [14] and are kept under control by peripheral tolerance mechanisms [15]. Probably the most important of these mechanisms is active regulation assured by regulatory T lymphocytes (Treg) capable of suppressing adaptive and innate immune responses [16], [17], [18].
The best-characterized Treg population is of CD4+Foxp3+ phenotype. However Treg populations that express CD8 or are CD4/CD8 “double negative” have also been described. The latter populations lack (unduly so and probably for historical reasons) the wide attention of immunologists. Scientists working on these populations face the difficult challenge to convince their colleagues of the relevance and importance of the field.
We will limit this review to murine CD8+ Treg, with reference to human counterparts when applicable. Similarly to CD4+ Treg, a distinction will be made between “natural” and “induced” CD8+ Treg populations. “Natural” Treg are cells that develop in the thymus, constitute stable lineages. “Induced” Treg are generated under experimental conditions and may or may not have stable phenotypes [19]. Several naturally occurring as well as induced immunoregulatory CD8+ T cell populations apparently using distinct effector suppressor mechanisms have been described (Table 1, Table 2). We will pay particular attention to a CD8+ Treg population characterized by the absence of CD28 expression and to its potential role in inflammatory bowel diseases.
Section snippets
Natural and induced CD8+ CD25+ Foxp3+ Treg in mice
In the CD4+ T cell population, the best characterized Treg population expresses CD25 and Foxp3. Similarly, among CD8+ T cells a small population of Foxp3-expressing CD25+ cells with in vitro regulatory capacity is found in the thymus and peripheral lymphoid organs of mice [20]. The phenotype of these CD8αβ cells is strikingly similar to their CD4+ counterpart. Most notably, they have an activated CD44high phenotype, express cell-surface molecules involved in suppressor effector functions of CD4+
CD8+ (CD75s+?) Treg induced by oral administration of antigen
Oral administration of self or nonself antigen leads to tolerance in a large variety of experimental models. Whereas other T-cell populations inhibiting or deviating immune responses are also involved, CD8+ Treg develop on oral antigen feeding [47]. Thus oral administration of myelin basic protein (MBP) led to reduced development of experimental autoimmune encephalomyelitis (EAE) [48]. Transfer of total but not of CD3- or CD8-depleted splenocytes from MBP-fed rats rendered adoptive hosts
CD8+ Treg development upon neonatal tolerance induction in rats
Th2-mediated autoimmune disease develops in susceptible rats upon subcutaneous injection of mercury salts. Neonatal subcutaneous administration of this heavy metal led to resistance to subsequent disease induction. The suppression was dominant and could be transferred with CD8+ (but not CD4+) splenocytes [58]. As compared with splenocytes from diseased rats, CD8+ splenocytes from tolerant animals were enriched in cells producing CD45RChigh, CD25+, IFN-γ, and IL-2. The immunosuppressive
Natural and induced CD8+ CD45RClow Treg in rats
In rats, CD8+ T cells with in vitro and in vivo suppressor activity were found in the CD45RClow population [59]. These cells were very similar, but not identical, to CD4+ Treg. As compared with “conventional” CD8+CD45RChigh cells, CD45RClow Treg transcribed Foxp3 and CTLA4, but not GITR genes at higher levels. In vitro, these cells inhibited proliferation and IFN-γ production in a cell-contact dependent manner; but, in contrast to CD4+ Treg, exogenous IL-2 did not reverse this suppressive
Natural CD8+ CD122high Treg in mice
Another natural CD8+ Treg population was discovered upon the description that CD122 (IL-2Rβ-chain)–deficient mice developed T-cell–mediated severe anemia [61]. Although other mechanisms may also apply, it was shown that the immunopathologic condition was at least in part caused by the absence of a regulatory CD8+CD122+ population [62]. We have observed that all mouse CD8+ T cells express CD122, but that a small subpopulation express very high levels [63]. Based on these results we will further
Intestinal CD8ααTCRαβ natural Treg in mice
In contrast to thymus-derived CD8+ cells, which express the CD8αβ hererodimer, the majority of CD8+ cells in the intestinal epithelium express a CD8αα homodimer. Although some TCRαβ CD8αα T cells with characteristics of innate immune cells can develop in the thymus upon interaction with high levels of agonist ligands [66], most TCRαβ CD8αα cells develop in the intestine. These cells have an oligoclonal but not canonical TCR repertoire enriched in autospecific cells [67]. TCRαβCD8αα
“Naturally induced” Qa-1–restricted CD8αα+ Treg in mice
Immune responses, even those directed to pathogens, need to be tightly controlled to avoid pathologic conditions and death (e.g., by septic shock). Thus the injection of superantigens, which activate large numbers of T lymphocytes, is followed by strong proliferation and then by disappearance of reactive cells. It was shown that CD8+ T cells restricted by the nonclassic MHC class Ib molecule Qa-1, an HLA-E homolog, played a role in control of the TCR Vβ3+ CD4+ T-cell response to the bacterial
CD8+ CD11c+ Treg in mice
Signaling through the co-stimulatory molecule CD137 (4-1BB) enhances CD8+ and reduces CD4+ T-cell responses. Administration of an agonist antibody to CD137 inhibits development of collagen-induced arthritis, a murine model for rheumatoid arthritis [80]. Suppression of arthritis could be transferred to adoptive hosts with CD8+CD11c+ T cells from protected animals. IFN-γ produced by Treg as well as IDO were shown to play crucial roles in this process. IFN-γ potentially induced IDO on macrophages
Natural CD8+ CD28− Treg in mice
CD28-deficient mice are resistant to active induction of EAE. Although this result would suggest a requirement of CD28 for induction of disease, depletion of CD8+ cells in CD28-deficient mice renders them susceptible [83]. In contrast, CD8-deficient mice develop more severe EAE than wild-type animals, and injection of CD8+CD28− (but not CD8+CD28+) T cells before disease induction lowers disease severity to wild-type levels. In vitro, CD8+CD28− cells inhibited IFN-γ production in mixed
Conclusion
The numerous reports discussed here clearly indicate a renaissance of the field of CD8+ Treg. Even if the term “regulatory” is imprecise and suggests that such cells may also have an activating function on immune responses, it rightfully suggests similarity with CD4+ Treg. Moreover, its use may help to overcome the bad feelings associated with the expression “suppressor” T cells. Several CD8+ Treg populations have been identified, some of which are phenotypically and functionally well
Acknowledgment
This work was supported by the Association François Aupetit (2007).
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I. Ménager-Marcq is currently at INRA, UMR 1225, Ecole Nationale Vétérinaire de Toulouse, Toulouse, France.