Although this paper does not deal specifically with arthritis, its relevance lies in the intriguing speculations it raises on the common basis for autoimmunity and tumor immunity. It suggests that a regulatory T cell controls both tumor specific and self-reactive T cells. Studies show that a subpopulation of CD4⁺ T cells prevents autoimmune disease in a number of rodent models. Many studies have previously suggested this regulatory T cell population is CD25⁺ CD4⁺, and is anergic (non-proliferative) in normal mice. Stimulation of the regulatory T cells suppresses the activation/proliferation of other CD4⁺ or CD8⁺ T cells in an antigen non-specific manner. Removal of CD25⁺ CD4⁺ T cells elicits autoimmunity, and enhances immune responses to non-self antigens such as allogeneic tissue grafts. Here the authors investigate the hypothesis that removal of CD25⁺ CD4⁺ immunoregulatory T cells may evoke immune responses to autologous tumor cells by allowing activation of anti-tumor effector cells. To investigate the role of immunoregulatory CD25⁺ CD4⁺T cells in tumor immunity.

Balb/c nu/nu mice were simultaneously given a Balb/c spleen suspension depleted of CD25⁺ cells (CD25-depleted) and RL1 tumor cells (subcutaneous transplant). Transfer of CD25-depleted cells allowed prolonged survival. Upon rechallenge with a larger RL1 dose, mice receiving CD25-depleted cells rejected tumor cells more rapidly. In vitro, CD25-depleted spleen suspensions (from tumor unsensitised mice) cultured with or without RL1, showed significant, promiscuous killing activity against both autologous, natural killer (NK)-resistant and allogeneic tumor cells. Two types of cytotoxic cells were isolated from protected mice: CD8⁺ CTLs, which killed autologous (RL1) tumor, and CD4^- CD8^- T cell receptor ^- NK1.1, which were responsible for the promiscuous killing activity. In vitro, generation of NK cytotoxic cells was dependent on a population of CD4⁺ CD25^- T cells. Blocking studies indicate these CD4⁺ T cells required self peptide/MHC class II complexes on antigen presenting cells. Exogenous IL-2 substituted for the effect of CD4⁺ T cells in generating CTLs. Mice which received CD25-depleted cell transfers rejected transplants, but developed autoimmune diseases including gastritis, thyroiditis and oophoritis. If CD4⁺ cells were eliminated from the CD25-depleted cell transfers, the mice did not develop autoimmune disease. Transfer of CD8⁺or NK CTLs alone did not result in autoimmunity.

This interesting paper presents evidence for the delicate balance between effective tumor immunity and autoimmune disease (such as gastritis, thyroiditis and oophoritis). A number of studies demonstrate that many tumor antigens are normal self-constituents, and are recognised by autologous cytotoxic T lymphocytes (CTLs). Moreover, cancer immunotherapy, by vaccination with tumor antigens or transfusion of CTLs, frequently elicits autoimmunity as a result of cross-reactions between tumor antigens and normal tissue antigens. Such findings suggest that autoimmunity is integral to tumor immunity. The authors thus speculate that breaking immunological self-tolerance (by removal of immunoregulatory CD25⁺ CD4⁺ T cells) may evoke effective tumor immunity in otherwise non-responding individuals, but risk onset of autoimmune disease.

Mice used were Balb/c, Balb/c-nu/nu, C57BL/6 (B6) C3H/HE and B6-beige (bg/bg). A number of studies used interleukin (IL)-2, IL-4 or interferon (IFN)-? gene knockout mice. Tumor cells were RL1 (Balb/c-derived radiation leukemia), B16 (B6-derived melanoma), X5563 (C3H-derived plasmacytoma) and P815 (DBA/2-derived mastocytoma). T cell subpopulations, prepared from spleen, were cultured in vitrowith or without mitomycin C-treated tumor cells, and were subsequently tested for cytotoxicity in a chromium release assay, or for proliferation and IL-2 production. Autoimmune disease was assessed by histological or serological tests for gastritis and thyroiditis.