CD4⁺CD25⁺regulatory T cells limit the risk of autoimmune disease arising from T cell receptor crossreactivity

Abstract

The molecular-mimicry theory proposes that immune crossreactivity between microbial and self-antigen is the initiating event in the activation of autoaggressive immune responses leading to autoimmune disease. In support of this possibility, it is now accepted that T cell recognition of antigen is highly degenerate. However, it is to be expected that the immune system would have evolved mechanisms to counter such a potential danger. We studied the influence of CD4 ؉ CD25 ؉ regulatory T cells (Treg) on the ability of suboptimal T cell receptor ligands to provoke autoimmunity. By using CD4 ؉ T cell-driven experimental autoimmune encephalomyelitis as a model, it was found that depletion of CD4 ؉ CD25 ؉ Foxp3 ؉ Treg allowed pathology to develop in response to suboptimal T cell stimulation. These data demonstrate the importance of Treg in raising the threshold of triggering of autoreactive T cell responses, thus limiting the risk of autoimmune disease due to molecular mimicry.experimental autoimmune encephalomyelitis (EAE) ͉ multiple sclerosis ͉ regulation ͉ tolerance E xtensive flexibility in T cell receptor (TCR) recognition of peptide-MHC (pMHC) complexes has been proposed to be essential to provide effective immune surveillance of all possible pathogen-derived pMHC complexes (1). The logical extension of this cross-reactivity is that the peripheral T cell repertoire should contain a sizeable population of cells that are capable of responding in a cross-reactive manner to both pathogen-derived antigens (Ags) and self-molecules. This concept is at the heart of the molecular-mimicry theory, in which self-reactive T cells, activated initially by infectious pathogens, subsequently provoke a self-destructive response in an organ expressing a crossreactive self-Ag (2). However, there is considerable debate over the validity of this theory as a general mechanism for the induction of autoimmune disease (3), and mechanisms that limit this potential risk are likely to exist. Naturally occurring regulatory T cells (Treg) may have a role by raising the activation threshold of T cell responses, potentially providing one mechanism by which weakly self-reactive T cells can be maintained in the T cell repertoire without inducing overt autoimmunity.Treg activity is enriched in the subset of CD4 ϩ T cells expressing CD25 in mice (4), rats (5), and humans (6), leading to the now widespread use of this marker to define a naturally occurring population of Treg. The influence of Treg on peripheral tolerance is shown most vividly by the widespread autoimmune and inflammatory lesions that are evident in humans and mice that lack these cells because of mutations in the Tregspecific transcription factor Foxp3 (7-10). Although conclusive evidence regarding the specificity of CD4 ϩ CD25 ϩ Foxp3 ϩ Treg remains elusive, they are known to have a broad TCR repertoire (11), and there is evidence to suggest that CD25 ϩ Treg developing in the thymus are selected to have high affinity for self-Ags expressed on thymic epithelium (12)(13)(14). Negative...

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

“…Our findings are consistent with the observation that anti-CD25 antibodies do not mediate FOXP3 expression in CD4 + CD25 − T cells [37]. However, the data presented here vary from the absence of compensatory expansion of CD25 − FOXP3 + T cells in response to anti-CD25 antibodies in a model of experimental autoimmune encephalomyelitis in wild-type mice [38]. Since anti-CD25 antibodies do not always deplete CD25 + T cells [27], but rather inhibit their function [37], the cytokine environment might be less favourable for expansion of the CD25 − FOXP3 + T cells [39].…”

In vivo depletion of CD4+FOXP3+ Treg cells by the PC61 anti‐CD25 monoclonal antibody is mediated by FcγRIII+ phagocytes

“…1 also [17]). In contrast to the original hypothesis, our data and several others [15,[17][18][19][20][21] have shown that PC61 mAb treatment does not completely remove Foxp3 1 Treg. In peripheral blood, $30% of Foxp3 1 Treg with low or no CD25 expression remain untouched by PC61 mAb (Fig.…”

“…In peripheral blood, $30% of Foxp3 1 Treg with low or no CD25 expression remain untouched by PC61 mAb (Fig. 1 also [17,19,21]). Nevertheless, the fact that PC61 mAb treatment elicits such a profound effect on immune responses indicates that partial elimination of Foxp3 1 Treg is sufficient to disrupt immunological balance between the regulators and the effectors.…”

Lack of Effective MUC1 Tumor Antigen-Specific Immunity in MUC1-Transgenic Mice Results from a Th/T Regulatory Cell Imbalance That Can Be Corrected by Adoptive Transfer of Wild-Type Th Cells

“…However, the adoptive transfer of MUC1-expanded CD4 ϩ CD25 Ϫ T cells from WT mice to MUC1-Tg mice to raise the level of MUC1-specific T cell help is a proof of principle that we believe can be applied to the clinic where patients would receive transfers of autologous Treg-depleted Th cells that are expanded to large numbers in vitro by stimulation with MUC1. Restoring the balance to the MUC1-specific immune response via the provision of a defined component, such as functional Th cells, may be a more feasible clinical approach to treating malignancies than global depletion of the patients' Tregs, which may be fraught with side effects such as autoimmunity (55)(56)(57)(58)(59)(60).…”