Regulation of tumour immunity by CD25+ T cells.

Abstract

The impact of the immune system on tumour growth in humans is poorly understood. Several studies have, however, identified T cells, in particular CD8+ cytotoxic T lymphocytes (CTLs), that recognize antigenic peptides expressed on autologous tumour cells.1,2 These tumour antigens include tumour-specific antigens that arise through mutations in normal genes; shared tumour antigens such as cancer–testis antigens; differentiation antigens; and other self-antigens that may be over-expressed in malignant cells. In some cases, where malignancies arise as a result of virus infection, tumour cells may also express viral antigens. Although antigens of each category have been found to act as targets for T-cell responses in human patients, the ability of these T cells to promote tumour rejection remains unproven.3 Experimental evidence obtained using murine models indicates that either CD4+ or CD8+ T-cell responses to certain tumour-associated self-antigens can indeed result in tumour rejection.4–7 Melanocyte differentiation antigens are the best-characterized self-antigens that act as targets for tumour (melanoma) rejection.8 Vigorous immune responses to melanocyte antigens have been shown to result, not only in tumour regression, but also in the development of autoimmune vitiligo. Vitiligo is a disease characterized by skin depigmentation following the destruction of non-malignant melanocytes, often by T cells.9 Overall, these findings indicate that the same effector T cells can be involved in both autoimmunity and tumour immunity. Thus, mechanisms of peripheral tolerance, which inhibit the activation of autoreactive T cells, also impinge upon the induction of T-cell responses to tumour-associated self-antigens. Several mechanisms account for the lack of reactivity of T cells specific for self-antigens. Many self-reactive T cells are deleted by mechanisms of negative selection in the thymus.10,11 Subsequently, some T cells that escape this process die following encounter with antigen in the periphery, whilst others survive but become functionally inactivated (anergic).12 Other self-reactive T cells, residing in lymphoid tissues, may be oblivious to self-antigens expressed in peripheral sites13 particularly in the absence of any pro-inflammatory stimuli.14 When, however, these cells do meet self-antigens through, for example, infection or tissue injury, other pathways may also be called upon to limit the activation of such cells. An increasing body of evidence indicates that the immunomodulatory potential of a population of CD4+ CD25+ T cells, named CD25+ regulatory cells, represents one such pathway.15,16