Novel T regulatory cells come of age: The curious incident of a mouse in Tennessee, delayed thymectomy and chimeric receptors!

Several seminal events built on years of basic discoveries led to recognition of the critical role of a subset of T cells, termed regulatory T cells or Tregs, in controlling both immunity and tolerance. The concept that immune responses could be controlled by T cells was first proposed by Gershon and Kondo in the 1970′s [1,2], the first year of publication of our journal. At the time they were called “suppressor cells”, with activity demonstrated primarily in phenomenological cell mixing experiments, but interpretations were limited by the lack of the markers and reagents we have today. This observation was followed by what might be referred to as a bandwagon effect of publications, but ended approximately 12 years later with a molecular analysis of so-called MHC linkage to “I-J” or lack thereof [3]. But with the end of suppressor T cells came the rise of Tregs, with the combined findings of Sakaguchi and colleagues on post-neonatal thymectomy [4], clinical observations of IPEX patients [5] and the cloning of FOXP3 [6], enabling a fortuitous link with the scurfy mouse, the latter being “the curious incident of the mouse in Tennessee” (https://www.youtube.com/watch?v = TfSI5WRwDXM)! The scurfy mutation occurred spontaneously in a mouse colony at the Oak Ridge National Laboratories during World War II, enabling the subsequent cloning of FoxP3 by Ramsdell and colleagues [7].

The current issue of CELLULAR IMMUNOLOGY contains 16 research and review articles that celebrate the current landscape of “Treg” research and highlight the emergence of novel approaches to enhance their efficacy. For example, several articles describe how antigen-specific CD4 + or CD8 + Tregs can be generated and expanded by applying approaches initiated by Zelig Eshhar in Israel [8] and applied clinically for cancer in the form of CAR (Chimeric Antigen Receptor) T cell therapy [9,10].

Thus, a major focus of this issue are reviews by Rosado-Sánchez and Levings [11], Janssens and Cools [12], and Rana and Biswas [13] that discuss the evolution of CAR-engineered Tregs. These articles emphasize the issues in generating and improving the design of specific Treg for use in transplantation, autoimmunity and hemophilia, for example. Savinov et al. [14] discuss the challenge of careful selection of chimeric receptors, a factor that is extremely important in the derivation of specific and non-specific Tregs for transplantation, as put forth by Alzhrani and colleagues [15].

Pohl et al. [16] and Fu et al. [17] present original research articles demonstrating the efficacy of scFv engineered Tregs and FoxP3-transduced expanded specific Tregs in experimental animal models for multiple sclerosis and hemophilia, respectively.

In their article, Mannie et al.[18] propose that the affinity of T cell recognition can modulate Treg function in designing tolerogenic vaccines. In addition, Planchais and colleagues [19] argue that the oxidative environment may alter the repertoire and behavior of B cells in driving autoimmunity. Osei-Bordom et al. [20] review the unique role of the liver as a driver of Tregs, while Bertolini and colleagues emphasize the involvement of the gut in driving oral tolerance via Tregs [21].

In their review on immune regulation in lymphopenic hosts, Waldmann and Graca [22] suggest a mechanism for “infectious tolerance” to explain the bystander effect of Tregs. Akkaya and Shevach [23] review how Tregs may be the master criminals of the immune system (like “Macavity, the Mystery Cat” in T.S. Elliot’s poem) [24] by not only stealing cytokines like IL-2, but also stripping membrane receptors off antigen presenting cells, although not necessarily disappearing as in the poem.

Reviews by Lees [25] and Li et al. [26] bring us back to appreciate how cytotoxic CD8 + T cells can also play an important role in in regulating undesirable responses in autoimmunity and adverse reactions to therapeutics.

Overall, the special issue of CELLULAR IMMUNOLOGY highlights both the multitude of ways that Tregs can act as conductors of the immunologic orchestra and the progress over the five decades since the discovery of “suppressor (T) cells” [1]