Engineered antigen-specific regulatory T cells for autoimmune skin conditions

Abstract

Regulatory T cells (Tregs) are a subset of T cells responsible for the regulation of immune responses, thereby maintaining immune homeostasis and providing immune tolerance to both self and non-self-antigens. An increasing number of studies revealed Treg numbers and functions in a variety of autoimmune diseases. Treg deficiency can cause the development of several autoimmune skin diseases including vitiligo, alopecia areata, pemphigoid and pemphigus, psoriasis, and systemic sclerosis. Many clinical trials have been performed for autoimmune conditions using polyclonal Tregs, but efficiency can be significantly improved using antigen-specific Tregs engineered using T cell receptor (TCR) or chimeric antigen receptor (CAR) constructs. In this review, we systematically reviewed altered frequencies, impaired functions, and phenotypic features of Tregs in autoimmune skin conditions. We also summarized new advances in TCR and CAR based antigen-specific Tregs tested both in animal models and in clinics. The advantages and limitations of each approach were carefully discussed emphasizing possible clinical relevance to patients with autoimmune skin diseases. Moreover, we have reviewed potential approaches for engineering antigen-specific Tregs, and strategies for overcoming possible hurdles in clinical applications. Thereby, antigen-specific Tregs can be infused using autologous adoptive cell transfer to restore Treg numbers and to provide local immune tolerance for autoimmune skin disorders.

Keywords: Antigen-specific; Autoimmune skin diseases; Chimeric antigen receptor; Regulatory T cells; T cell receptor.

Fig. 1.

Autoimmune etiology of autoimmune skin diseases. (a) Illustration of immune surveillance in healthy skin. Adoptive transfer of antigen-specific Tregs to control (b) autoimmune depigmentation in vitiligo, (c) autoimmune blistering of the skin in pemphigus vulgaris, (d) autoimmune psoriatic patches in psoriasis, (e) autoimmune hair loss in alopecia areata, (f) autoimmune fibrosis in systemic sclerosis.

Fig. 2.

Scheme for Adoptive Treg transfer. (a) Leukapheresis of lymphocytes from peripheral blood of the patient. (b) Polarization of CD4⁺ T cells in to FOXP3⁺ Tregs in the presence of TGF-β. (c) Viral transduction of FOXP3⁺ Tregs with either TCR or CAR construct. (d) Tregs transduced with TCR and CAR construct. (e) Ex vivo expansion of Tregs to generate sufficient numbers for adoptive Treg transfer. (f) Sorting for Tregs using either magnetic or FACS based methods. (g) Infusion of either TCR or CAR Tregs into patients.