A step closer to the clinic

As the concept of regulatory T (T_Reg) cells has become widely accepted during the past ten years, there has been increasing interest in their therapeutic potential to inhibit inappropriate immune responses, such as autoimmune diseases. However, the low frequency and unknown specificity of naturally occurring CD4⁺CD25⁺ T_Reg cells limit their immediate application. These two papers show how these problems might be overcome in two animal models of autoimmunity — type 1 diabetes and experimental autoimmune encephalomyelitis (EAE; a model of multiple sclerosis).

Jaeckel et al. show that, rather than isolating the small numbers of naturally occurring T_Reg cells from a patient, transduction of abundant naive CD4⁺ T cells with the T_Reg-cell-associated transcription factor FOXP3 (forkhead box P3) can be used to induce a regulatory phenotype. Foxp3-transduced polyclonal CD4⁺ T cells from non-obese diabetic (NOD) mice produced the regulatory cytokine interleukin-10 after stimulation with CD3-specific antibody and suppressed the proliferation of naive CD4⁺CD25⁻ responder cells in co-culture. However, these Foxp3-transduced polyclonal T cells had no effect on disease when transferred to NOD mice with recent-onset diabetes. A therapeutic effect was only obtained when the T cells to be transduced with Foxp3 were isolated from T-cell receptor (TCR)-transgenic mice that recognize a pancreatic-islet antigen. Such T cells showed specific homing to, and activation in, the pancreatic draining lymph nodes, indicating that the antigen specificity of the T_Reg cells will be important in determining therapeutic efficacy.

One potential method for redirecting the antigen specificity of polyclonal T_Reg cells is described by Mekala and Geiger. They transgenically modified the T_Reg cells with a chimeric receptor consisting of a myelin basic protein (MBP) epitope bound to the extracellular and transmembrane domains of MHC linked to the cytoplasmic domain of the TCR ζ-chain. Such receptor-modified T cells specifically recognize, and are activated by, T cells specific for the MBP epitope. Receptor-modified CD4⁺CD25⁺ T cells inhibited both the onset and development of EAE induced with MBP but not with another known EAE autoantigen. The authors suggest that combining this technique with Foxp3 transduction could be used to generate a population of antigen-specific T_Reg cells from the peripheral-blood T cells of a patient.