T cell exhaustion and immune-mediated disease — the potential for therapeutic exhaustion
Introduction
The clinical course of immune-mediated disease is highly variable — two individuals presenting with the same diagnosis may subsequently follow markedly different clinical courses, ranging from frequent relapses, disease progression and death to long-term stable remission with minimal treatment. While many studies have focussed on the factors predisposing to the onset of autoreactivity [1], there has been little consideration of the factors controlling disease course once autoimmunity is established. It is now becoming clear that the biology underlying a relapsing or quiescent disease course may be largely distinct from that which predisposes to broken self tolerance in the first place [2, 3••]. This biology has been historically neglected, in part because it requires the more demanding, prospective collection of long-term follow-up data. Its relevance to treatment strategies is, however, arguably more pertinent — it may prove more tractable to modulate pathways controlling a chronic autoimmune response than to strive to restore tolerance itself.
While these strategies are partially overlapping, recent observations that analogous responses to chronic antigen occur during chronic viral infection, autoinflammatory diseases and the anti-tumour response have suggested the potential for a new framework for modifying chronic inflammatory disease through modulation of a process known as T cell exhaustion.
Section snippets
Definition and evolution of exhaustion
Following transient exposure to antigen, such as during acute viral infection, antigen-specific T cells undergo rapid proliferation followed by a more prolonged contraction phase. Following this, the population of memory cells that remain confer protective immunity, characterised by higher proliferative potential, a reduced activation threshold and the ability to persist long-term in the absence of cognate antigen [4]. However, where antigen persists, such as during chronic viral infection, CD8
Manipulating exhaustion: checkpoint blockade and agonists
While CD8 exhaustion is known to limit viral control during chronic infection, exhausted cells may also be restored to useful function by blocking inhibitory signalling through PD-1, resulting in reduced viral loads even in the absence of a CD4-helper response [12••]. In addition, immune checkpoint therapy targeting exhaustion-associated T cell inhibitory receptors restores effective anti-tumour T cell responses, producing a durable clinical response in a subset of patients [19]. Such
Exhaustion, anergy and senescence
While exhausted CD8 cells retain the capacity to differentiate in to robust memory cells [12••], other states of T cell dysfunction such as anergy and senescence do not show similar plasticity. Exhausted CD8 T cells can be reinvigorated by transfer from chronically LCMV-cl13 infected to uninfected mice (although this potential is ultimately lost later in the course of persistent infection) [24]. This observation highlights the role of complex CD8-extrinsic inhibitory signals from multiple
Reversing exhaustion, inducing immune-mediated disease
Exhaustion has likely evolved to protect the host from collateral immunopathology that would accompany a robust attempt to eradicate a chronic virus. Exhaustion may therefore work in the hosts favour, at least during non-cytopathic viral infection (e.g. LCMV, HBV, HCV) where the immediate consequences of ‘tolerating’ the virus are not problematic. Clearly, avoiding early immunopathology does come at a cost, however, as permitting chronic infection brings different long-term problems (such as
Inducing exhaustion, controlling immune-mediated disease?
As a state of CD8 exhaustion shows plasticity and may be reversed, we have proposed that it may be possible to induce T cell exhaustion as a novel therapeutic approach for autoimmune disease. This concept is supported by observations that a transcriptional signature of exhaustion associates with protection from a relapsing course in multiple autoimmune diseases [3••], that LCMV-cl13 infection can prevent the onset of virally induced autoimmunity in a mouse expressing a viral transgene as an
The challenge of inducing exhaustion
Therapeutic induction of T cell exhaustion in autoimmunity is a logical proposition. However, there are several important caveats to consider. Firstly, reversal of CD8 T cell exhaustion is facilitated by persistent high-level expression of the inhibitory receptors promoting it — in other words, there is a clear surface receptor target to block. In order to promote exhaustion, a checkpoint agonist must target robustly costimulated memory-like CD8 cells that, by definition, express only minimal
Conclusions
CD8 T cell exhaustion has been associated with clinical outcome in immune-mediated disease. It is plausible that in chronic inflammatory disease, as in chronic infection and cancer, exhaustion is not just associated with outcome, but dictates it. Consequently, therapeutic induction of T cell exhaustion represents a novel strategy to achieve improved long-term control of immune-mediated disease and remains of focus of ongoing research.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by The National Institute of Health Research (NIHR), Cambridge Biomedical Research Centre, the Wellcome Trust (project 094227/Z/10/Z and program grants 083650/Z/07/Z), a Lister Prize Fellowship (KGCS) and the Lupus Research Institute (Distinguished Innovator Award, KGCS). EFM is a Wellcome–Beit Research Fellow supported by the Wellcome Trust and Beit Foundation (104064/Z/14/Z).
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