UVInduced Suppressor Regulatory T Cells

UV-induced skin tumors from UV-suppressed mice grow progressively when transferred to mice immunocompromised by UV, yet typically regress when transplanted into immunocompetent mice (Fisher and Kripke 1978, 1982, Kripke et al. 1979). Furthermore, the transfer of T lymphocytes from UVB-irradiated mice into healthy recipients also results in the failure to reject UVB-induced tumors (Spellman and Daynes 1977, Spellmann et al. 1977). Analogous results were obtained using the hapten model of sensitization (Elmets et al. 1983, Noonan et al. 1981), in which injection of T lymphocytes from lymph nodes or spleens originating from UVB-irradiated and hapten-sensitized mice suppress CHS responses in the recipients. In correlation to the studies previously mentioned, the recipients could still generate a normal CHS response to a non-cross-reacting hapten (Elmets et al. 1983, Noonan et al. 1981). Taken together, these findings corroborate the hypothesis that UV-induced tolerance is mediated via induction of hapten-specific suppressor T cells. Yet, because of the poor characterization of the molecular mechanisms and the phenotypes of the cells generating these suppressive phenomena, the term "suppressor T cells" was almost banned and the entire concept of suppression drawn into question (Shevach 2001, 2002). However, the persistent hunt for suppressor T cells by investigators in pho-

toimmunology and other fields finally resulted in the discovery of these regulatory T cells, thus justifying both the search for and the concept of suppressor T cells (Chate-noud et al. 2001, Shevach 2001, 2002).

Tolerance can be induced by the transfer of lymphocytes in both local and systemic suppression. However, different subsets of T cells seem to be responsible for the immunosuppressive effects. Systemic UVB-induced suppression (see "UV-Induced Systemic Immunosuppression") is mediated by antigen-specific CD3+, CD4+, and CD8- suppressor cells (Elmets et al. 1983, Ullrich et al. 1990). The results of a study initiated by Elmets et al. (Elmets et al. 1983) revealed that in local UV-induced immunosuppression, treatment of cells from UVB-irradiated animals with antibodies directed against Lyt-1 (CD4) completely abrogated their ability to transfer suppression, whereas treatment of cells with antibodies directed against Lyt-2 (CD8) inhibited suppression partially. Accordingly, Schwarz et al. (Schwarz et al. 1998) reported that in the UV low-dose model, suppression was prevented when the transferred T lymphocytes were depleted of CD8+ cells. It is important to note that suppressor T cells in this particular experimental design influence the induction but not the elicitation of CHS, since introduction of UVB-induced suppressor T cells into previously sensitized mice does not affect the CHS response in recipients (Glass et al. 1990, Schwarz et al. 2004). This observation might indicate that effector T cells dominate suppressor T cells.

On the heels of the discovery of suppressor T cells, the field of immunosuppression and suppressor T cells has experienced a tremendous revival. Many studies have been conducted to further characterize this cell type. Both human and murine CD4+ T cells subjected to chronic activation with CD3 in the presence of IL-10 induce CD4+ T-cell clones with low proliferative capacity, low levels of IL-2, and no IL-4, yet are able to produce high levels of IL-10 (Shevach et al. 2001). Studies in severe combined immunodeficient (SCID) mice demonstrated that these antigen-specific T-cell clones can suppress the proliferation of CD4+ T cells in response to antigen and can be used to prevent T-cell-mediated colitis (Groux et al. 1997, Sakaguchi et al. 1995). This particular subset of CD4+ T cells was designated regulatory T cells. Another subset of CD4+ regulatory T cells is characterized by the constitutive expression of the a chain of the IL-2 receptor (CD25) (Chatenoud et al. 2001, Sakaguchi et al. 1995, Shevach 2001). Interestingly, CD4+CD25+ regulatory T cells constitute approximately 10% of all human and murine peripheral CD4+ T cells. The results of these and other studies have inspired a great deal of new research investigating the role of suppressor/regulatory T cells, currently making this area of research one of the most intensively studied subjects in general immunology. Whether the cells are termed "regulatory" or "suppressor" is more a matter of semantics, but because of this new breakthrough, the concept of suppressor T cells has been redeemed and is now "socially accepted" in the immunologic community (Chatenoud et al. 2001, Shevach et al. 2001).

The first successful cloning of regulatory T cells from UVB-irradiated mice was achieved by Shreedhar et al. (Shreedhar et al. 1998b). Mice were sensitized with fluo-rescein isothiocyanate after UVB treatment. The T cells cloned from these mice were phenotypically analyzed as CD4+, CD8-, TCR-a/p+, MHC-restricted T cells specific for the fluorescein isothiocyanate antigen. They secreted IL-10 but not IL-4 or interferon-^, whereas cells from nonirradiated control animals produced high amounts of interferon-y and little IL-4 and IL-10 (Shreedhar et al. 1998b). The cytokine pattern of the UVB-induced cells was related but not identical to that of T regulatory 1 cells; thus, the authors designated these cells as T regulatory 2-type cells. In vitro experiments established that these cells can block antigen-presenting cell functions, including IL-12 production. Even more important, injection of precisely these now-characterized T cells into untreated recipients suppressed the induction of CHS against fluorescein isothiocyanate.

Although many studies previously pointed the finger at suppressor T cells of the CD8 type, the previously mentioned reports and many more provide increasing evidence that most belong to the CD4 type. In this respect, the role of CD4+CD25+ regulatory T cells in eliciting UVB-induced tolerance remains to be determined. First, clues as to the importance of CD4+ T cells in generating UVB-induced immunosup-pression were recently found using major histocompatibility complex class II knockout mice (Krasteva et al. 2002). These animals are resistant to the immunosuppressive effects of UVB irradiation, indicating that UVB-induced immunosuppression is due to preferential activation of CD4+ suppressor/regulatory T cells and a result of deficient priming or expansion of effector CD8+ T cells (Krasteva et al. 2002).

T-suppressor cells also express the negative regulatory molecule cytotoxic T-lym-phocyte activation molecule-4 (CTLA-4) on their surfaces. CTLA-4 is functionally relevant for immunosuppression because inhibition of CTLA-4 by a neutralizing antibody inhibits the induction of tolerance and immunosuppression after the transfer of T cells (Schwarz et al. 2000). In vitro stimulation of suppressor T cells induces the release of IL-2, interferon y, high amounts of IL-10 but no IL-4, a cytokine secretion pattern reminiscent of that of regulatory T cells. Evidence for one possible mode of action by which CTLA-4 could exert its effects, namely, by the induction of IL-10, results from the observation that transfer of suppression was inhibited when recipients received neutralizing anti-IL-10 antibodies.

As is now fairly obvious, there is a distinct heterogeneity of suppressor cells, and this becomes even more apparent by the observation that UVB-induced natural killer T (NKT) cells are involved in the suppression of tumor immune responses (Moody-cliffe et al. 2000). NKT cells express intermediate amounts of T-cell receptor molecules and co-express surface antigens usually found on natural killer cells (NK1.1, DX5, and Ly49a). Moodycliffe et al. supplied compelling data that UVB-induced suppressor T cells may actually belong to the NKT type and that these cells can suppress DTH and antitumoral immunity. It remains to be seen to what extent these cells, which have also been detected in UV-exposed humans, play a role in the etiology of tumor progression of UVB-induced skin cancers (Hersey et al. 1983).

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