A Possible Way to Target Exhausted T-Cells For Destruction

Researchers here identify a possible way to identify and target T-cells that clutter up the aged immune system, impacting its effectiveness. A sizable part of immune decline in aging seems to result from the accumulation of large numbers of memory T-cells and exhausted or anergic T-cells at the expensive of naive T-cells capable of attacking threats. This may be due to the presence of cytomegalovirus, CMV, which is very prevalent and largely harmless, except for the fact that it cannot be cleared from the body and over the years the immune system devotes ever more of its limited resources to the problem.

This issue has a blunt solution: destroy the useless and the excess T cells, freeing up space for new competent immune cells to be generated as replacements. The basic concept has been demonstrated for other parts of the immune system; destruction of old, bad B cells led to the creation of fresh new B cells in animal studies, for example. A range of targeted cell destruction technologies are at various stages of development in the cancer research community, many of which can be coupled to arbitrary detection and delivery mechanisms. A whole field of research revolves around building future standards for platforms that can join a cell-killer to a sensor and delivery mechanism that discriminates targets by their particular surface chemistry. The first step on this road is finding a useful characterization of the target:

In acute infections, antigen-specific T cells differentiate into activated effector cells and then into memory T cells which rapidly gain effector functions and re-expand on subsequent encounter with the same pathogen. In contrast, during chronic infections, pathogen-specific T cells gradually lose effector functions, fail to expand, and can eventually become physically deleted. These traits are collectively termed T cell exhaustion, and have been described both in animal models of chronic viral infection as well as in human infections with hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Identifying reversible mechanisms of T cell exhaustion is therefore a major goal in medicine.

Discovering surface markers of exhausted T cells is important for both to identify exhausted T cells as well as to develop potential therapies. We report that the ectonucleotidase CD39 is expressed by T cells specific for chronic viral infections in humans and a mouse model, but is rare in T cells following clearance of acute infections. In the mouse model of chronic viral infection, CD39 demarcates a subpopulation of dysfunctional, exhausted CD8+ T cells with the phenotype of irreversible exhaustion.

In this study, we demonstrate that, in contrast to CD8+ T cells from healthy donors, antigen-specific CD8+ T cells responding to chronic viral infection in humans and a mouse model express high levels of biochemically active CD39. CD39+ CD8+ T cells co-express PD-1 and are enriched for a gene signature of T cell exhaustion. In the mouse model of chronic LCMV infection, high levels of CD39 expression demarcate terminally differentiated virus-specific CD8+ T cells within the pool of exhausted CD8+ T cells. Thus, CD39 provides a specific, pathological marker of exhausted CD8+ T cells in chronic viral infection in humans and mouse models of chronic viral infection.

Link: http://dx.doi.org/10.1371/journal.ppat.1005177

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