Tregs in T cell vaccination: exploring the regulation of regulation

Abstract

T cell vaccination (TCV) activates Tregs of 2 kinds: anti-idiotypic (anti-id) and anti-ergotypic (anti-erg). These regulators furnish a useful view of the physiology of T cell regulation of the immune response. Anti-id Tregs recognize specific effector clones by their unique TCR CDR3 peptides; anti-id networks of CD4+ and CD8+ Tregs have been described in detail. Here we shall focus on anti-erg T regulators. Anti-erg T cells, unlike anti-id T cells, do not recognize the clonal identity of effector T cells; rather, anti-erg T cells recognize the state of activation of target effector T cells, irrespective of their TCR specificity. We consider several features of anti-erg T cells: their ontogeny, subset markers, and target ergotope molecules; mechanisms by which they regulate other T cells; mechanisms by which they get regulated; and therapeutic prospects for anti-erg upregulation and downregulation.

Figure 1

The balance between Treg loss (red arrows) and Treg renewal (green arrows). Resting Tregs can be activated by recognizing a specific ergotope presented in either of 2 ways: by an activated effector T cell or by a professional APC (yellow cell). The interaction between the activated Treg (green cells) and the activated effector T cell (purple cells) leads to inactivation of the effector T cell but also to anergy of the Treg (white cells). Thus, presentation of ergotopes by activated T cells leads to Treg loss. In contrast, an ergotope presented by a professional APC activates Treg proliferation and cycling (Treg renewal).

Figure 2

Autoimmune disease through Treg loss and health through Treg renewal. Environmental factors (viral infection, toxic chemicals, trauma, etc.) can lead to triggering of an excess number of autoimmune effector T cells. These induce Treg anergy (see Figure 1) and Treg loss. The autoimmune effector excess can then bring about an autoimmune disease. In contrast, T cell and/or ergotope vaccination can activate Treg renewal (see Figure 1). The enhanced numbers of activated Tregs can inactivate autoimmune effector T cells, leading to the restoration of health.

Figure 3

Immune evasion by tumors or infectious agents could take place by excess Treg renewal, resulting in suppression of specific effector T cells. Anti-Treg vaccination could restore health by inducing Treg loss, leading to effector T cell renewal and rejection of the tumor or infectious agent.