Therapeutic modulation of cutaneous autoimmunity by regulatory T cells
Department of Dermatology, University of Münster, D-48149 Münster and 1Interdisciplinary Clinical Research Center (IZKF), Münster, Germany.
Correspondence to: Stefan Beissert, MD, Department of Dermatology, University of Münster, Von-Esmarch-Strasse 58, D-48149 Münster/Germany. E-mail: beisser{at}uni-muenster.de
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Abstract |
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Cutaneous autoimmunity is characterized by the presence of autoantibodies and/or autoreactive T cells. Several mechanisms have been developed to avoid loss of immunotolerance to self such as activation-induced cell death, deletion, ignorance and active suppression of autoreactivity. Regulatory (‘suppressor’) T cells play a pivotal role in inhibiting the activation and function of effector T cells. CD4+CD25+ T cells constitute a subset of regulatory T cells, which have been shown to suppress the development of organ-specific autoimmunity in mice. Recent understanding in the generation and function of human regulatory T cells indicates that these cells are involved in the appearance of inflammatory as well as bullous autoimmune dermatosis. These findings suggest that modulation of regulatory T cell numbers or function might be a promising therapeutic alternative for the treatment of such disorders. In the following, recent strategies aimed at inducing antigen-specific or non-specific regulatory T cells for the immunotherapy of ongoing cutaneous autoimmunity are presented and discussed. Hopefully, pursuing these strategies in the future will result in the initiation of randomized clinical studies analysing the usefulness of regulatory T cells for human skin diseases in great detail.
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The role of regulatory T cells in immunity |
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The immune system has developed to fight infection. To achieve this goal, discrimination between self and non-self is of utmost importance. Immunocompetent cells can bind microbial antigens via Toll-like receptors (TLR) and initiate innate immune responses, which are highly conserved response patterns to combat microbes. Upon infectious encounter, biological information becomes imprinted as immunological memory resulting in a rapid response during re-challenge with the same infectious agent at a later time point. This so called adaptive immune reaction is mediated by antigen-presenting cells (APC), such as dendritic cells, B cells and macrophages, which take up antigens and present them upon processing to naïve T cells. However, during inflammation and tissue damage, APC present foreign and autoantigens with the potential to initiate autoreactivity.
Regulatory T cells have been shown to play an important role in the inhibition of self-reactivity. The discovery that CD4+CD25+ T cells can prevent the development of multiorgan autoimmunity upon injection together with CD4+CD25– T cells into immunodeficient SCID mice has sparked research on regulatory T cells, which is currently one of the most competitive fields in immunology [1]. CD4+CD25+ T cells are the best characterized population of regulatory T cells, which constitute 
6–9% of CD4+ T cells in mice and man. Human and murine CD4+CD25+ T cells develop in the thymus, and the transcription factor that controls CD4+CD25+ T cell development is Foxp3. In vitro CD4+CD25+ T cells can suppress the activation of CD4+CD25– T cells via a cell-contact-dependent mechanism involving granzyme B and the tryptophane metabolism [2, 3]. Regulatory T cells are anergic upon T cell receptor (TCR) stimulation; however, co-culture with interleukin-2 (IL-2) stimulated their proliferation. Several other molecular markers have been identified for regulatory T cells such as cytotoxic T lymphocyte antigen-4 (CTLA-4), CD62L, CD45RBlow, CCR4, CCR5 and CCR8, some of which are functionally important. The crux with some of these markers, including CD25, is that they are also expressed during T cell activation and are thereby difficult to use for the discrimination between regulatory and recently activated T cells. Gene expression profiling revealed neuropilin-1 as an ideal marker to study regulatory T cells in mice, since neuropilin-1 is not up-regulated upon activation [4].
Analysis of regulatory T cells revealed that the TCR repertoire is similar between regulatory and effector T cells, suggesting that, indeed, regulatory T cells are responsive to self. In murine models using antigens with known specificity, it was shown that regulatory T cells can be induced by APC, especially dendritic cells. Injection of fusion proteins, which were able to bind to CD205 (Dectin-205) on dendritic cells, induced CD4+CD25+ T cells with regulatory function [5]. Moreover, immature dendritic cells can, upon repetitive co-incubation with naïve T cells, stimulate suppressor function in vitro. In addition, mature dendritic cells were able to expand peripheral numbers of regulatory T cells, after injection into transgenic mice. Together, these findings demonstrate that APC play an important role in the maintenance of regulatory T cells.
It is increasingly clear that several subsets of regulatory T cells exist. Besides CD4+CD25+ T cells also CD4+CD25–, NKT, Th3, type 1 regulatory (Tr1) and CD8+ T cells with suppressor function have been identified. These findings show that the mere need to identify the existence of regulatory T cells has been now replaced by the need to understand their role in disease development to, perhaps, be able to therapeutically manipulate their function.
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Regulatory T cells in human skin diseases |
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In autoimmunity, activation of regulatory T cell function seems to be appropriate to control disease development. Treatment of patients at the beginning of type 1 diabetes with humanized anti-CD3 antibodies resulted in the inhibition of disease progression [6]. It was proposed that besides activation-induced cell death of autoreactive T cells, also the stimulation of regulatory T cells contributed to the beneficial therapeutic effects. Perhaps activation of regulatory T cells by anti-CD3 antibody injections could prevent also other diseases where lack of function or low numbers of regulatory T cells has been described. In psoriasis vulgaris, low peripheral numbers of regulatory T cells have been detected, and isolation of these cells from psoriatic lesions showed decreased suppressor function [7]. A severe form of psoriasis is psoriatic arthritis, which can lead to the destruction of joints. Thus, patients suffering from psoriasis or psoriatic arthritis might benefit from the application of anti-CD3 antibody treatment.
Pemphigus vulgaris is a rare acquired autoimmune blistering disease where autoantibodies to the desmosomal protein desmoglein-3 (Dsg-3) mediate disease by inducing loss of keratinocyte adherence. On the one hand, Dsg-3 autoreactive T cell clones have been identified in pemphigus patients, which could provide T cell help to B cells to become Dsg-3 autoantibody producing plasma cells. On the other hand, Dsg-3+ Tr1 cells have been detected in patients and healthy HLA-matched individuals. Interestingly, in pemphigus patients, lower numbers of Tr1 cells with reduced suppressor function were present compared with healthy individuals [8]. There are recent experiments being performed to isolate Dsg-3+ Tr1 cells from patients and to expand them in vitro. This could be achieved either by co-culture with dendritic cells pulsed with the cognate antigen, Dsg-3 or by adding high concentrations of IL-2 together with TCR stimulation to the culture conditions. Those expanded autologous Dsg-3+ Tr1 could then be reinfused into the same pemphigus patient to control disease alone or in combination with (low-dose) immunosuppressive therapy.
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Strategies to develop regulatory T cells for cell therapy |
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A difficulty in the development of regulatory T cells for cell therapy is their low yield. In an attempt to circumvent this problem, several methods have been developed to generate regulatory T cells in vitro. In one report, CD4+CD25– T cells have been infected with a retrovirus containing the transcription factor Foxp3. Foxp3-infected CD4+ T cells showed a low proliferative response to TCR stimulation. Moreover, Foxp3-infected, but not control-virus-infected, CD4+ T cells were able to inhibit the proliferation of naïve CD4+CD25– T cells. These findings suggest that infection with Foxp3 containing retrovirus conferred a regulatory phenotype on CD4+ T cells. In addition, since CD4+CD25– T cells can be isolated for retroviral infection in numbers sufficient for cell therapy, this method seems to be promising to generate CD4+ T cells with suppressor function in vitro.
To test whether Foxp3-infected CD4+ T cells are able to suppress T cell-mediated contact hypersensitivity (CHS) responses, groups of sensitized mice were injected with either Foxp3- or control-virus-infected T cells. Upon challenge with the contact allergen, only the latter were able to mount significant CHS responses. In contrast, injection of Foxp3-infected CD4+ T cells reduced CHS responses significantly [9]. These results indicate that in vitro-generated Foxp3 expressing CD4+ T cells can be successfully used to suppress contact allergy.
In almost all published reports on the function of regulatory T cells, the suppressor function was shown as suppression of the activation of naïve CD4+CD25– T cells or as inhibition of the initiation of for example, colitis in mice. The question remains whether regulatory T cells are able to control ongoing immune responses. Therefore, Foxp3 expressing CD4+ T cells were injected into CD40L transgenic mice after onset of overt systemic autoimmunity [10]. After 6 weeks of treatment, disease score was reduced significantly in CD40L transgenic mice that received Foxp3 containing CD4+ T cells, indicating that, indeed, in vitro-generated regulatory T cells can be successfully used to control ongoing systemic autoimmunity [9]. Furthermore, treatment with Foxp3+ CD4+ T cells reduced autoantibody titres below detectable concentrations and greatly improved renal function as evidenced by the decreased proteinuria. Together, these findings indicate that regulatory T cells are promising candidates for the treatment of unwanted immune responses.
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Acknowledgement |
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Many publications could not be cited due to space restrictions; we apologize to their authors. This work was supported by grants from the Germany Research Association (DFG; SFB 293 B8) and the Interdisciplinary Clinical Research Center (IZKF; Lo2/065/04).
S. B. received speaker's honorarium for participation at Actelion Winter School 2006.
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References |
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