T cell exhaustion refers to their dysfunction

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Just as it is for marathoners who’ve completed a 26-mile run, or shrubs that have gone without water in a heatwave – exhaustion is an unavoidable fact of life.

Dogs get exhausted after herding sheep; birds turn in for the night after an exhausting day of flying and singing. The same is true for T cells, the workhorses of the immune system – they get exhausted, too.

As more investigators turn their attention to this extraordinary phenomenon – T cells too fatigued to function—an international team of investigators foresees the possibility of reversing the exhaustion. The aim is to reinvigorate cellular warriors that have been beaten down by germs or sucker punched by tumor cells and rendered too worn out to fight.

T cell exhaustion refers to their dysfunction, caused by chronic antigen stimulation. Antigens are proteins from infectious agents or tumor cells, recognized by healthy T cells as foreign – and dangerous. Antigens are the reason T cells pull out all the stops as they mount an immune response to eliminate offenders.

Putting up a powerful and sustained response can have disabling, even fatal consequences. T cells react to foreign antigens through their receptors – T cell receptors – or simply, TCRs. The receptors recognize and respond to antigens through potent signaling capabilities.

But antigen overstimulation of TCRs – as is common in major persistent infections – can damage T cell signaling and exhaust the TCRs’ ability to respond effectively to threats.

In a joint investigation involving scientists from the United States and Japan, researchers took an in-depth look at T cell exhaustion to find out why and when it occurs. Additionally, they identified a key protein embedded in the T cell surface, a transmembrane protein that serves as a marker of T cell exhaustion. Under conditions of widespread fatigue the transmembrane protein, named Tim-3, singularly signifies T cell exhaustion, the scientists found.

The presence of this transmembrane protein stands as powerful evidence that persistent and overwhelming antigen exposure results in the exhaustion of TCR signaling, even the deletion of vast numbers of T cells. These warriors can become exhausted under the constant pressure of fighting an offender that can’t be easily knocked out.

“Because the transmembrane receptor Tim-3 is increased in abundance on exhausted T cells, it is thought to inhibit T cell activation and is being considered as a therapeutic target to reinvigorate antitumor responses,” wrote Drs. Lawrence P. Kane and Shunsuke Kataoka, authors of a T cell exhaustion study in the journal Science Signaling.

Lane is a researcher at the University of Pittsburgh. Kataoka studied at the university as a graduate student but also is on staff at Asahi Kasei Pharma Corporation in Shizuoka, Japan. They worked with a multi-disciplinary team at the University of Pittsburgh and found that Tim-3 not only serves as a marker for T cell exhaustion, but surprisingly also stimulates some exhausted T cells to resume signaling.

Using various imaging techniques, the international team demonstrated that Tim-3 is recruited to T cell immune synapses, the critical points of contact between T cells and antigen-presenting cells, such as sites of contact with dendritic cells (which literally present T cells with antigens of invaders that have breached the body).

Because of Tim-3’s influence, enhanced signaling can resume downstream for some TCRs. Despite the resumption, it apparently is not enough to reinvigorate armies of exhausted T cells. But now that it’s known how some T cells are revived, it’s theoretically possible to intervene with a pharmaceutical boost.

Investigations into T cell exhaustion are not new research endeavors. Some studies date back nearly 30 years. An animal study from 1993, for example, examined viral persistence in acutely infected, immunocompetent mice. Viral persistence led to exhaustion of antiviral cytotoxic effector T cells, researchers found.

Even though immunologists first described T cell exhaustion occurring in response to chronic viral infection, they found the powerful T cell response to cancers can result in TCR dysregulation, too.

Exhaustion has been well documented in various subpopulations of T cells. A substantial amount of research has been devoted to CD8+ T-cells, particularly the subpopulation known as cytotoxic T cells, which are critical in the destruction of cancerous or virally infected cells. CD4+ T cells also have been shown to develop functional unresponsiveness after chronic infections.

The very act of fighting long-term infiltrators can irrevocably sap the strength of T cells. This is especially true when T cells are caught in a battle royal thwarting infectious diseases of significant public health concern: Hepatitis B and C, or HIV, the human immunodeficiency virus.

Beyond the research by Lane, Kataoka and the team at the University of Pittsburgh, two studies published in the journal Nature Immunology recently drilled down on possible causes of T exhaustion and suggested possible ways to reverse it. And while Lane and Kataoka, suggested that reinvigorating T cells could reboot antitumor responses, a team at Massachusetts General Hospital in Boston, looked into possible rejuvenation of T cells damaged by the persistence of a viral disease.

Dr. Georg M. Lauer of Massachusetts General launched a study that investigated T cell fatigue as a result of hepatitis C infection.

After patients in his study were treated and cured, Lauer and colleagues discovered that exhausted disease-fighting T cells had transformed in ways that made them resemble memory T cells, suggesting antiviral therapy potentially played a role in T cell transformation. Yet, the cells didn’t function as well as genuine memory T cells, the study found.

Lauer said in a statement that “a more superficial study could have been interpreted as real recovery, whereas in reality the key parameters determining the efficacy of a T cell were unchanged.” He added that timing the drug differently may have a stronger impact on sparing T cells.

“We are currently studying whether treating HCV with direct-acting antiviral therapy in the acute phase of infection, instead of many years later, will result in full memory differentiation of T cells. If correct, this could indicate a short window of opportunity early during chronic infections to protect T cell function,” he said.

Lane and Kataoka, are riveted on Tim-3’s increased abundance as a biomarker on exhausted T cells, which they consider a potential therapeutic target. By pharmaceutically targeting Tim-3’s ability to reboot signaling, T cells theoretically could resume antitumor activity, the scientists say.


What do we mean by T cell exhaustion and/or dysfunction and how would you define this state?
Nicholas P. Restifo and Rachel C. Lynn.

It is important to start off by stating that the term ‘T cell exhaustion’ is a basket term that describes various distinct epigenetic and metabolic states of post-thymic T cells. This term was popularized by viral immunologists and anthropomorphizes chromatin states that are characteristic of mice experiencing chronic viral infection, mainly with lymphocytic choriomeningitis virus (LCMV), where T cells are thought to be unable to clear a chronic infection.

Axel Kallies and Dietmar Zehn.

The term ‘exhaustion’ is used mainly to refer to effector T cells with a reduced capacity to secrete cytokines and increased expression of inhibitory receptors. These cells were thought to be hypofunctional effector T cells that differentiate from normal effector T cells in response to a chronically high antigen load. However, several observations have challenged this view and suggest that exhausted T cells are heterogeneous, have crucial roles in limiting viral infection or tumour growth1 and may develop independently from normal effector T cells, as outlined in the responses below (FIG. 1).

Fig. 1 |
The knowns and unknowns of T cell exhaustion.
Potential developmental relationships between and features of exhausted T cell subsets compared with effector and memory T cell suswbsets during chronic versus acute antigen stimulation.

W. Nicholas Haining and Arlene H. Sharpe.
When an infection cannot be cleared by the host, a détente can occur whereby pathogen-specific T cells curtail their antipathogen function to avoid causing damage to normal tissues. Importantly, T cell exhaustion does not involve the complete absence of function: exhausted T cells can proliferate in vivo2, produce effector molecules, including inflammatory cytokines and granzymes, and exert some control over pathogens or tumours3.

E. John Wherry.
I agree that T cell exhaustion is an evolutionarily conserved adaptation to chronic antigen stimulation that is probably important to limit immunopathology or autoreactivity; thus, exhausted T cells are not inherently good or bad.

Pamela L. Schwartzberg.
Yes, although exhaustion is often seen as a dysfunctional state, it also allows T cells to persist and partially contain chronic infections without causing immunopathology.

Mary Philip and Andrea Schietinger.
Like our colleagues, we define T cell exhaustion as a differentiation state that is observed during chronic infections in the presence of persistent antigen and chronic T cell receptor (TCR) stimulation. Exhausted T cells express inhibitory receptors but can retain some antipathogen effector function, resulting in a pathogen–host ‘stalemate’4.

E.J.W.
There is general consensus that some features of exhausted T cells, compared with effector or memory T cells, include altered, sometimes reduced, effector functions, such as decreased (but not absent) cytokine production; increased chemokine expression; persistently high levels of expression of multiple inhibitory receptors, such as PD1, TIM3, LAG3, CTLA4 and TIGIT; reduced proliferative capacity when stimulated; an altered transcriptional programme involving the transcription factor TOX; and a unique epigenetic landscape4.

N.P.R. and R.C.L.
Chronic TCR signalling as a core mechanistic driver of exhaustion is highlighted by the well-established role of the calcineurin-dependent transcription factor nuclear factor of activated T cells (NFAT)5 and other NFAT-driven, TCR-responsive transcription factors (such as IRF4, BATF, nuclear receptor subfamily 4 group A (NR4A) and TOX)6–12 in both upregulating the expression of inhibitory receptors and maintaining the long-term survival of exhausted T cells.

Patrick G. Hogan and Anjana Rao.
We believe that for both tumour-infiltrating and virus-specific T cells, the most useful definition of exhaustion is an operational one: when exhausted T cells are present in the same environment or are stimulated under the same conditions as fully functional effector T cells, they have reduced responses (are hyporesponsive) to antigen. In addition to the features described in the responses above, it might also be worth expanding the definition of exhausted T cells to include criteria such as reduced levels of signalling proteins associated with activation and/or increased levels of negative regulatory proteins such as diacylglycerol kinases, phosphatases and E3 ubiquitin ligases13,14.

Enrico Lugli and Benjamin A. Youngblood.
We think it is important to note that although many investigators assign exhaustion status to T cells simply on the basis of their expression of inhibitory receptors, this is not a definitive feature of exhausted T cells as many highly functional effector T cells also express inhibitory receptors.

M.P. and A.S.
Another caveat to consider is that although antigen-specific T cells in tumours have many immunophenotypic and molecular features of exhausted T cells in chronic infection, they often completely lack effector function and fail to control tumour growth; therefore, we refer to these T cells as being dysfunctional rather than exhausted15.

Christian U. Blank and Ton N. Schumacher.
Instead, we would rather argue that the analysis of T cells in human and mouse tumours by single-cell sequencing and functional assays has provided strong evidence that T cells with high levels of expression of inhibitory receptors should not be considered exhausted (meaning ‘used up’ or inert) but rather should be considered dysfunctional or divergent (by which we mean that they have assumed an unconventional functional state). For example, this is shown by the ongoing proliferation in part of this T cell pool and the capacity of these cells to produce the chemokine CXCL13 (REFS16–18). Human tumours can contain large numbers of bystander T cells, and intrinsic tumour reactivity (the presence of a tumour-reactive TCR) is enriched among cells with a dysfunctional phenotype19,20. Although the in vivo development of a dysfunctional state was initially described under conditions of chronic antigen exposure21,22, the fact that dysfunctional T cell states are observed early after tumorigenesis23 and viral infection7,24, and can be induced by removing CD4+ T cell help25, suggests that the quality of costimulatory and/or inhibitory signals during TCR triggering may be an equally important factor.

N.P.R. and R.C.L.
We agree that the epigenetic state of T cells in chronic viral infection is similar but not identical to the epigenetic state of tumour-infiltrating lymphocytes (TILs), which are exposed to additional stimuli that may contribute to their dysfunction, including metabolites or lack thereof, immunosuppressive cytokines and chemokines and ionic disturbances. Thus, exhausted T cells are dysfunctional, but not all dysfunctional T cells are exhausted. Alternative mechanisms are at work, particularly in the case of TILs. We think it would be more constructive to use tumour systems to describe the epigenetic states of exhausted TILs rather than extrapolating from LCMV infection to describe these states.

Werner Held and Daniel E. Speiser.
As can be seen from the answers to the following question, recent studies have suggested that there are two distinct subsets of exhausted T cells — a progenitor (or precursor) subset, which has variably been referred to as being stem cell-like and/or memory-like, and a terminally differentiated subset. In contrast to some of our colleagues, we use the term ‘exhausted’ to refer only to the subset of chronically stimulated PD1+ cells that has limited recall expansion capacity and reduced effector functions (despite the expression of effector genes) and is irreversibly differentiated.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286441/


More information: Shunsuke Kataoka et al, The costimulatory activity of Tim-3 requires Akt and MAPK signaling and its recruitment to the immune synapse, Science Signaling (2021). DOI: 10.1126/scisignal.aba0717

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