Regulatory T‐cells: receptors, repertoires and roles in disease

Summary

In the 20‐or‐so years that immunologists have spent describing the mechanisms and functions of regulatory T‐cells, a very great deal has been learnt: a T‐cell subset once described for the generic ability to harness autoimmunity in vivo or diminish T‐cell proliferation in vitro is now appreciated to act on a plethora of cellular pathways using a diverse array of mechanisms. Recent studies have shed new light on basic and applied aspects of Treg function, including T‐cell receptor usage, specialist functions of tissue‐resident Tregs, and the therapeutic consequences of tuning Treg function up or down for applications in autoimmunity or cancer, respectively.

As Immunology celebrates its 60th birthday, making it one of the oldest dedicated immunology journals, we were minded to look back at our most highly cited papers over these many years. Near the top of this list was Martin Raff's 1970 description of using immunofluorescence microscopy to distinguish two new subsets of lymphocytes that would come to be known as T‐ and B‐cells,1 and a 1971 paper from Gershon and Kondo, on ‘infectious immunological tolerance’. This was the initial description of what were then termed T suppressor cells.2

Older readers will appreciate the double‐edged reputation of this paper: on the one hand, Dick Gershon was one of the great thinkers of 20^th century immunology, and should be credited with the landmark observation that a population of T‐cells must be policing the other cells to keep them in check and maintain self‐tolerance. On the other hand, T suppressor cells were subsequently to be expunged from the textbook – the field became mired in recrimination with the observation that the I‐J region of the major histocompatibility complex (MHC), supposed to control T suppressor cells, did not exist. It took the best part of a decade for the phenomenon of immune regulators to be tentatively reappraised, now with the advantage of more robust models and reagents, and badged as regulatory T‐cells, Tregs.3, 4 While some of the functions overlapped with T suppressor cell studies, the discredited notion of an MHC‐encoded, antigen‐specific suppressor factor had been replaced largely by the short‐range effects of regulatory cytokines such as IL‐10 and TGFβ, as well as effects on metabolism and apoptosis.

Molecular immunology studies of recent years have generated an explosion of knowledge in the Treg field, with enormous ramifications for therapeutics in clinical disease, if one could only conquer the art of tuning up or down this regulation to order. A key area of investigation has been in the rules of antigen recognition by the T‐cell receptor (TCR) of Tregs. Are they looking at the same antigen set in the same way as T effector cells, or do they have special rules of engagement? Tregs are presumed to be targeted during thymic selection to recognition of self‐antigens, but notwithstanding efforts in some elegant model systems, definition of the ligand set that induces Treg cell differentiation remains elusive.5 Clues as to the rules of differential TCR engagement of Treg cells have come from high‐throughput analysis of TCR repertoires.6 Bulky CDR3 loops are more prominent in the Treg TCR pool than in T effector cells, in line with the model for Tregs as cells with enhanced affinity for self‐peptide–MHC complexes.

Considering the diverse functions of Tregs with ever‐improving granularity, a key issue has been to define the differential roles of tissue‐resident subsets in different niches, a question at the heart of understanding the cross‐talk between Tregs and their local environment. Seen in this light, there may be less appetite for analyses of Tregs from peripheral blood as generic exemplars of all Tregs, with more attention to studying the differential features of cells at specific sites. A key example is the role of localized Tregs in the gut in controlling immune recognition of gut microbiota antigens and so preventing inflammatory disease.5, 7

The skin offers challenges of immune control that are in some respects similar to the gut, comprising a massive, microbiota‐colonized, mucosal interface, at constant risk of immune dysregulation and inflammation.8 In both humans and mice, Tregs comprise a considerable subset of all skin‐resident cells, emphasizing the paramount importance of regulation at this site. Lymphoid follicles are a specialized niche offering a rather different kind of challenge of immune regulation: the function of Tregs here is to control the size of the germinal centre and the amount and affinity of antibodies produced, so limiting the opportunity for autoantibody‐mediated disease.9 The suppressive mechanism of T follicular regulatory cells here seems to involve the CTLA‐4‐dependent modulation of T follicular helper cells and germinal centre B‐cell metabolism.

Tumours constitute another specialized niche, with variable ability to promote their own survival through the enhanced representation of Tregs among infiltrating cells.10 In line with this, anti‐tumour CTL responses are often improved by depletion of Treg cells, an observation that forms the basis for several current anti‐tumour therapies. As protocols advance for tumour therapy using checkpoint blockade approaches based on the PD‐1 pathway, it will be advantageous to develop further insight into preferential manipulation of these interactions in effector versus regulatory cells.11

While improved tumour therapies may depend on developing precise tools to tune‐down tumour Tregs relative to effectors, the challenge in autoimmunity or transplant rejection will be to enhance regulation. This has been an area of exciting translational progress. Clinical trials using approaches such as transfer of expanded Tregs have been reported in a range of diseases, including type 1 diabetes.12

This truly is an exciting time for Treg immunology, with game‐changing, new clinical therapeutics just on the horizon.13 There have been rumours that an imminent Nobel Prize may be awarded for Treg research. Let us hope that the Nobel Committee's commendation remembers to cite the fact that this field of regulation started with a rather contentious little paper in Immunology all those years ago.