Peripheral CD8+ T Cell Tolerance to Self-Proteins Is Regulated Proximally at the T Cell Receptor

Abstract

CD8(+) T cell tolerance, although essential for preventing autoimmunity, poses substantial obstacles to eliciting immune responses to tumor antigens, which are generally overexpressed normal proteins. Development of effective strategies to overcome tolerance for clinical applications would benefit from elucidation of the immunologic mechanism(s) regulating T cell tolerance to self. To examine how tolerance is maintained in vivo, we engineered dual-T cell receptor (TCR) transgenic mice in which CD8(+) T cells recognize two distinct antigens: a foreign viral-protein and a tolerizing self-tumor protein. Encounter with peripheral self-antigen rendered dual-TCR T cells tolerant to self, but these cells responded normally through the virus-specific TCR. Moreover, proliferation induced by virus rescued function of tolerized self-tumor-reactive TCR, restoring anti-tumor activity. These studies demonstrate that peripheral CD8(+) T cell tolerance to self-proteins can be regulated at the level of the self-reactive TCR complex rather than by central cellular inactivation and suggest an alternate strategy to enhance adoptive T cell immunotherapy.

Abrogating Cbl-b in effector CD8+ T cells improves the efficacy of adoptive therapy of leukemia in mice

“…The E3 ubiquitin ligase, Casitas B-lineage lymphoma b (Cbl-b), is a negative regulator of lymphocyte function (12)(13)(14)(15). Cbl-b increases the threshold for naive T cell activation by regulating TCR and CD28 signaling, in part by inhibiting PKCθ-and PI3K/Akt-dependent pathways, respectively (16)(17)(18)(19)(20).…”

“…However, these studies are not directly applicable to human therapeutic settings, as current adoptive therapy protocols require expanding the small numbers of tumor-reactive T cells isolated from the host in vitro via multiple cycles of stimulation to produce adequate numbers of differentiated effector cells for infusion (23). In the disseminated Friend murine leukemia virusinduced (FMuLV-induced) FBL leukemia therapy mouse model (24), adoptive transfer of large numbers of in vitro expanded CD8 + TCR transgenic T cells (TCR gag cells) specific for an epitope derived from the gag protein of FMuLV that is expressed by FBL tumor cells is insufficient to mediate tumor regression, unless -similar to the requirement for efficacy in human clinical trials -injections of exogenous IL-2 are provided to promote persistence of transferred T cells (14,(25)(26)(27). The requirement for a prolonged T cell response in this model provides an ideal setting for testing the efficacy of strategies designed to improve T cell activation, proliferation, and persistence.…”

Antibody-mediated B-cell depletion before adoptive immunotherapy with T cells expressing CD20-specific chimeric T-cell receptors facilitates eradication of leukemia in immunocompetent mice

“…Persistent exposure to CD20 on B cells may also impair CD20-specific cTCR ϩ T-cell survival. T cells are anergized or deleted in environments characterized by abundant major histocompatibility complex-restricted antigen derived from neo-self antigens, 7,8 tumor antigens, 9 or chronic viral infections. 10 Although B cells can exhibit tolerogenic properties when stimulating naive T cells, little is known about in vivo reactivation of effector T cells by antigen-expressing naive B cells.…”

The SCHOOL of nature: I. Transmembrane signaling

“…6 and 7, stage 2). This dissociation mechanism provides a structural and mechanistic basis for our improved understanding of many immunological phenomena, such as adaptive T cell tolerance or anergy, [185][186][187][188][189][190][191] differential biological role of CD3 chains, 192 ligand-or antibody-induced exposure of a cryptic polyproline sequence in the CYTO domain of CD3ε, 165,[193][194][195] BCR desensitization, [196][197][198][199] human cytomegalovirus (CMV) escape from NK attack 200 and others. The dissociation mechanism also allows the initially formed signaling oligomers to sequentially homointeract with the signaling subunits of nonengaged receptors (Figs.…”