Although such cells have the upon contact with self or cross-reactive antigens to expand, activate, and cause autoreactivity ultimately leading to autoimmune disease, several inactivating mechanisms exist to prevent this. Each of these lymphocyte subsets suppresses anti-DNA antibody production and delays the onset of nephritis in BWF1 lupus-prone mice. Patients with SLE have amino acid sequences similar to those from murine anti-DNA antibodies used in these studies, and at similar locations in the VH regions of anti-DNA immunoglobulins. Therefore, strategies described here might ultimately be useful in therapy of the human disease. Keywords:systemic lupus erythematosus, CD8+T cells, regulatory T cells, suppressor T cells == INTRODUCTION == Because systemic lupus erythematosus (SLE) depends on the production of auto-antibodies by B cells driven by helper T cellsa process that occurs in a milieu of permissive cytokines, chemokines, and sex hormones influencing interactions between cell surface receptors and their ligandsinterruptions of any of these circuits are likely to alter disease. Our laboratory has focused on interrupting helper T cellB cell interactions in the (NZB/NZW)F1 (BWF1) murine lupus model via induction of immune tolerance to immunoglobulin-based peptides, which calls up regulatory and suppressive T cells. == CONTROL MECHANISMS THAT PREVENT AUTOREACTIVITY IN HEALTHY INDIVIDUALS == In recent years there has been great interest in the role of regulatory/suppressive T cells in preventing and controlling autoimmunity.1There are several natural mechanisms for controlling autoreactivity. Many T cells with high avidity for self-antigens are deleted in the thymus (negative selection). T cells with relatively low avidity for self are likely to enter the peripheral immune system (positive selection), where they are closely regulated by peripheral tolerance mechanisms in healthy individuals. Although such cells have the potential upon contact with self or cross-reactive antigens to expand, activate, and cause autoreactivity ultimately leading to autoimmune disease, several inactivating mechanisms exist to prevent this. The mechanisms of peripheral tolerance include (a) activation-induced death, which occurs in T and B lymphocytes that receive very strong activating signals, capable of activating Fas/FasL interactions or tumor necrosis factor receptor (TNFR)-family death receptors; (b) anergya state in which T and B cells cannot secrete cytokines or immunoglobulins after activation, particularly if they receive signals only through their T cell receptor (TCR) or B cell receptor (BCR) without second signals through CD40/CD40 ligand (CD40L) pathways or CD28/CD80:CD86; (c) cytokine production that suppresses autoimmunity, including IL-4, IL-10, and transforming growth factor (TGF); and (d) active suppression by antigen-specific T cells.1,2Our work has focused on this last mechanism, the induction of T cells that actively suppress autoimmunity. == T CELLS INVOLVED IN SUPPRESSION == T cells that can suppress T and/or B cells include NK T cells, CD4+CD25+regulatory T cells, and CD8+suppressors (Table 1). Many CD8+T cells suppress responses in a largely antigen-nonspecific manner, but recent data have suggested that some subsets can operate via mechanisms that involve antigen recognition.1,3The induction of CD8+suppressor/effectors from precursor cells requires interaction with certain CD4+T cell subsets, which in certain cases can be activated T cells expressing Qa-1 (an MHC class Ib molecule that can present autologous or exogenous peptides to CD8+T cells).1,4,5In turn, the target cells downregulated by CD8+suppressors probably include CD4+Qa-1+antigen-specific CD4 recognized by the TCR of the CD8+suppressors.6There are several different types and/or mechanisms of action of CD8+T cell suppressor/effectors (Ts). These include cytotoxic T cells that require cellcell contact, cells that secrete cytokines (TGF-, interferon [INF]-) that induce apoptosis or death in their targets, and D77 Ts cells that interact with antigen-presenting cells (APCs) to render them tolerogenic, that is, D77 capable of producing anergy in CD4+helper T cells and of inducing CD4+CD25T regulatory cells.3,68There are examples of two types of D77 CD8+Ts cells protecting against SLE-like disease in NZB/NZW F1 (BWF1) lupus-prone mice, as discussed below. Further-more, recent experiments in our laboratory have shown that as BWF1 mice age, their peripheral CD8+T cells become increasingly defective. 9CD8+T cell populations in Rabbit polyclonal to A1CF these mice do not expand as dramatically as do CD4+cells, and only small proportions of CD8+T cells express activation and memory surface markers. In contrast, such markers are found on the majority of BWF1 CD4+T cells. When activated, significantly higher proportions of BWF1 CD8+T cells from older mice undergo apoptosis compared with CD8+T cells from young, healthy BWF1 mice or other nonlupus murine strains. Therefore, abnormal elimination of activated CD8+suppressor cells probably contributes to the failure of BWF1 mice to regulate autoantibody production and to their predisposition to SLE. == TABLE 1. == Characteristics of T D77 cells that control autoimmunity Murine CD4+T cells contain not only helper cells and suppressor-inducers, but also direct suppressors.1,1014These cells, now termed regulatory T cells.