TIGIT as a Therapeutic Target and Marker of T Cell Senescence and Exhaustion

In the open access paper here, researchers propose TIGIT as a marker of T cell senescence and exhaustion, also known as anergy, in the aged immune system. Further, this is not just a marker, but also a potential therapeutic target, as an initial test of lowered levels of TIGIT resulted in restoration of some measures of lost function in T cell populations with large degrees of senescence and exhaustion. These two forms of T cell dysfunction are not the same thing, but they do have overlapping features, and seem to be connected in a number of ways. In general, such cells perform poorly and behave badly. They show up to increasing degrees in the aged immune system, and play their part in its inflammatory, weakened state.

Much of the research into immune system aging leads to the conclusion that selectively destroying immune cells is helpful. An old immune system is a zoo of breakage and malfunction: too many senescent and exhausted cells; too many cells uselessly specialized to persistent viruses, particularly cytomegalovirus; autoimmunities of many varieties, outright or subtle, some poorly understood or yet to be recognized; and so forth. These problems are to a very large extent within the immune cells themselves. Thus a clean sweep to start over is not a bad idea, or at the very least removal of the known worst classes of malfunctioning immune cell, but these approaches currently lack an implementation safe enough to be used in older people. The only way of doing this at present is high dose treatments with immunosuppressive drugs, optionally followed by cell therapy to rebuild the immune system more rapidly than would other wise happen. This has been shown to cure the autoimmune condition multiple sclerosis, but bears a significant mortality risk, judging from the studies to date.

Distinctly from considerations of the immune system, the discovery of novel markers of cellular senescence is an interesting topic these days. Senescent cells are firmly identified as a cause of aging, producing general effects such as an increase in chronic inflammation, but also tissue- and type-specific effects that are largely detrimental. Senescent cells do assist in wound healing and cancer suppression, but these are transient duties, and the cells that linger afterwards quickly become a liability. Given a novel marker for cellular senescence, or cellular senescence in a specific cell type, it is a fairly slow and expensive process to figure out a pharmaceutical strategy to target it. But one of the companies in the space, Oisin Biotechnologies, has a programmable gene therapy that can in principle be triggered by high levels of any protein of interest inside a cell. Given this sort of capability, the path towards a successful attack on any new and interesting target can be much shorter than it used to be.

T-cell Immunoglobulin and ITIM Domain Contributes to CD8+ T-cell Immunosenescence

Immunosenescence is the age-associated dysregulation of the immune system, of high clinical relevance, as it contributes to multiple age-related comorbidities, including malignancies, infectious diseases, autoimmune diseases, and degenerative diseases. T cells are important components of the immune system. Age-associated T-cell dysfunction is important for the development of immunosenescence.

T-cell senescence is different from T-cell exhaustion, a hyporesponsiveness associated with chronic infections and cancer. Exhausted T cells are derived from activated T cells that progressively lose function because of persistent antigen stimulation, whereas senescence is cell cycle arrest due to aging. However, emerging evidence indicates that T-cell senescence shares several key features with exhaustion. The upregulation of multiple co-inhibitory receptors is not only a hallmark, but also an important mechanism involved in the development of T-cell exhaustion. Consistently, certain co-inhibitory receptors such as programmed cell death protein 1 (PD-1), T-cell immunoglobulin domain and mucin domain 3 (TIM-3), lymphocyte activation gene 3 (LAG-3), and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) are upregulated on T cells from aged mice, and blockade of PD-1 partially restores the functional defect of T cells derived from these mice. This finding indicates a pivotal role of T-cell inhibitory receptors in immunosenescence.

T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) is a recently identified co-inhibitory receptor that is expressed on activated T cells, regulatory T cells, and natural killer cells. Similar to CTLA-4 and CD28, TIGIT competes with its costimulatory counterpart CD226 for the same ligands (CD155 and CD112) and mediates immune suppression in tumors and chronic infections. Here, we investigated the role of TIGIT in human immunosenescence using blood samples from healthy adults.

As senescent and exhausted T cells exhibit similar features of immune dysfunction, it has been speculated that these two processes share common mechanisms. Studies show that a number of co-inhibitory receptors, including PD-1, TIM-3, LAG-3, and CTLA-4, are associated with impaired T-cell function in aged mice. However, we did not observe a correlation between these co-inhibitory receptors and aging in humans. The discrepancy highlights the limitations associated with the use of animal models in studies of immune senescence. Instead, we found a significant upregulation of TIGIT expression on T cells from elderly healthy donors compared with that from young individuals. The difference was more prominent in CD8+ T cells. TIGIT+ CD8+ T cells expressed high levels of other inhibitory receptors and displayed multiple functional defects, including reduced cytokine production and susceptibility to apoptosis. These data suggest that TIGIT is a biomarker and elucidate a potential mechanism of T-cell senescence. To the best of our knowledge, this is the first evidence linking TIGIT to immunosenescence.

The upregulation of TIGIT in the cohort started early and became worse with age, which indicated that T-cell senescence exists not only in the elderly but also in young individuals. Although senescence is thought to be associated with the physiological aging process, chronic activation, stimulation, or damage may accelerate T-cell senescence. A high percentage of senescent T cells is observed in young patients with chronic viral infections and autoimmune diseases. It remains unclear whether the age-dependent upregulation of TIGIT is associated with a physiological process or pathogenic stimulation. It is possible that TIGIT-associated T-cell senescence is a consequence of physiological stimulation. Moreover, despite TIGIT expression in the young and middle-aged, TIGIT+CD8+ T cells in the elderly were more dysfunctional than the population from the young and middle-aged groups, especially regarding defective cytokine production.

To study a direct effect of TIGIT in T-cell dysfunction, we performed a TIGIT knockdown experiment using siRNA and evaluated the T-cell functions upon TIGIT knockdown. We found a significant increased cytokine release and less apoptosis in CD8+ T cells from elderly subjects upon TIGIT knockdown. This important data demonstrate the suppressive effect of TIGIT in T-cell function in the elderly.

Recent studies demonstrated that TIGIT suppresses antiviral and antitumor CD8 T-cell immunity. Our novel observation that TIGIT is highly expressed on senescent T cells led us to speculate that TIGIT contributes to the functional defect of these T cells and subsequently increases the susceptibility to infection or cancer. In conclusion, the present study demonstrated that TIGIT is a prominent negative immune regulator involved in immunosenescence. This novel finding is highly significant, as targeting TIGIT might be an effective strategy to improve the immune response and decrease age-related comorbidities.

Comments

The object is to produce a healthy self-maintaining immune system that protects us from cradle to grave/and or immortality. Perhaps we should follow or at least consider the old axiom of not throwing the baby out with the bath water. If the adult immune system only has one or a few bad actors like TIGIT, we can knockout those gene SNP's that contribute to the immunosencescence, rather than destroying the entire immune system and starting over.

Posted by: Biotechy at January 27th, 2018 9:35 AM

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