Taking regulatory T cells into medicine

Abstract

Regulatory T cells (Tregs) are indispensable for the establishment and maintenance of immunological self-tolerance. Their genetic anomalies or variations in function are causative of various monogenic and polygenic autoimmune diseases. Treg-based reestablishment of self-tolerance is envisioned to cure autoimmune diseases in the clinic.

Shimon Sakaguchi

Tregs in immunological self-tolerance and autoimmunity. (A) Various autoimmune diseases can be induced in T cell–deficient rodents by simply transferring CD4⁺ T cell suspensions depleted of a subpopulation, for example, in mice, by depleting CD5^hiCD4⁺ T cells (Sakaguchi et al., 1985) and in rats, by depleting CD45RC^loCD4⁺ T cells (Powrie and Mason, 1990). Further efforts to delineate Tregs by more specific molecular markers led to the discovery of Tregs as CD25⁺CD4⁺ T cells, which are included in CD5^hi and CD45RC^loCD4⁺ T cells (Sakaguchi et al., 1995). Depletion of CD25⁺CD4⁺ T cells indeed resulted in spontaneous development of a wide spectrum of histologically evident autoimmune diseases such as autoimmune gastritis with anti-parietal cell autoantibody (shown here by indirect immunofluorescence staining of normal mouse gastric mucosa), autoimmune thyroiditis, and type 1 diabetes. (B) The majority of FoxP3⁺ Tregs constitutively expressing CD25 and CTLA-4 are produced by the thymus (tTregs), while some differentiate from Tconvs in the periphery (pTregs). Foxp3⁺ Tregs can also be induced in vitro from naive Tconvs (iTregs). Conversion of disease-mediating effector/memory T cells into functionally stable pTregs or iTregs (dotted line) can be ideal for antigen-specific suppression of pathological immune responses.