Suppressor T cell memory. II. The role of memory suppressor T cells in tolerance to human gamma globulin.

Abstract

The precise mechanism(s) of immunological tolerance to both self-and non-selfantigens remains unclear, despite substantial advances in the understanding of cellular and molecular immunology over the past three decades. Current hypotheses may be divided into two broad (but not necessarily mutually exclusive) categories: (a) those involving direct, antigen-induced clonal inactivation of specific T and/or B cells, and (b) those in which suppressor T cells (Ts) 1 are held to be responsible for specific unresponsiveness. The first category includes classical clonal deletion as described originally by Burnet (1) and modified subsequently by Bretscher and Cohn (2) in their "two signal" hypothesis. According to the latter, contact of an antigen-reactive cell with antigen alone (signal one) in the absence of a second triggering signal from a collaborating cell (signal two) leads to irreversible inactivation of the cell concerned. Related to this are certain variations (3, 4) of Lederberg's original hypothesis of selftolerance (5) which stated that developing lymphocytes are more sensitive than mature cells to antigen-induced inactivation. In some in vitro models receptor blockade has also been invoked as a mechanism for clonal inactivation (6), although this appears to be reversible (7) and its significance in vivo is uncertain.In the second category of hypotheses, antigen-specific (or in some cases idiotypespecific) suppressor cells are held to be responsible for initiating and maintaining tolerance. Although Ts have been shown to be present in a wide variety of unresponsive states (8-13), their precise role in the induction and/or maintenance of unresponsiveness remains controversial. One of the major reasons for this uncertainty is the repeated observation that the kinet.ics and magnitude of suppressive activity do not parallel the time course and degree of tolerance (14-16). Thus some investigators have come to regard the presence of Ts as a regulatory epiphenomenon of little or no relevance to the mechanism of immunological unresponsiveness (15,17,18).In this communication, Ts specific for the protein antigen human gamma globulin (HGG) have been shown to exist in two distinct functional states in tolerant animals, effector cells and memory cells. The activity of the former is readily apparent in standard adoptive mixing experiments shortly after tolerance induction, but their *

Generation and decay of the immune response to a progressive fibrosarcoma. II. Failure to demonstrate postexcision immunity after the onset of T cell-mediated suppression of immunity.

“…This study has shown, in addition, that the diminished capacity for generating concomitant immunity is associated with an ability to regenerate suppressor T cells in an accelerated manner, indicating the possession of "memory suppression" as recently shown by results from another laboratory (14). The persistence of this long-lived state of T cellmediated immunosuppression in the apparent absence of antigen, likens tumorinduced immunosuppression to immunological tolerance of the type that can be generated against histocompatibility antigens (15,16). For it is now well established that tolerance of histocompatibility antigens is actively sustained by suppressor T cells that enable it to be passively transferred to appropriate recipients (17).…”

Neonatal peptide exposure can prime T cells and, upon subsequent immunization, induce their immune deviation: implications for antibody vs. T cell-mediated autoimmunity.

“…Control animals immunized with p106 in CFA produce a predominant Thl-like response. Although Ag exposure in neonatal life has been suggested to result in clonal inactivation, deletion, or suppressor cell induction (3)(4)(5)(6)(7)(8)(9)(10), our data support "immune deviation" as a major mechanism of neonatal tolerance.…”

“…Neonatally induced T cell unresponsiveness has been at-tributed to several mechanisms, including clonal deletion and/or anergy of Ag-reactive cells (6)(7)(8)(9)(10), or generation of specific suppressor or regulatory cells (2,4,5). Most work on neonatal tolerance suggesting clonal deletion or inactivation as its mechanism has been based on the inability to mount Ag-specific T cell responses, either proliferative, or proliferative and helper for Ab production, after subsequent antigenic challenge (1)(2)(3)(7)(8)(9)(10).…”

Mechanisms of Neonatal Tolerance Induced in an Animal Model for Primary Sjögren's Syndrome by Intravenous Administration of Autoantigen

“…Animal models of T-cell-mediated autoimmunity have demonstrated that pathogenic responses can be both prevented and treated via the administration of autoantigen, and that this can be accompanied by several different mechanisms [1±6]. Neonatally induced T-cell unresponsiveness has been attributed to several mechanisms, including clonal deletion of antigen-reactive T cells [4±6, 25,26] and generation of suppressor or regulatory T cells [1,27,28]. Previous work on neonatal tolerance suggesting clonal deletion or inactivation has been based on the inability to mount antigen-speci®c T-cell responses.…”