Abstract
Cytotoxic CD8+ T cells (CTLs) contain virus infections through the release of granules containing both perforin and granzymes. T cell ‘exhaustion’ is a hallmark of chronic persistent viral infections including HIV. The inhibitory regulatory molecule, T cell Immunoglobulin and Mucin domain containing 3 (Tim-3) is induced on HIV-specific T cells in chronic progressive infection. These Tim-3 expressing T cells are dysfunctional in terms of their capacities to proliferate or to produce cytokines. In this study, we evaluated the effect of Tim-3 expression on the cytotoxic capabilities of CD8+ T cells in the context of HIV infection. We investigated the cytotoxic capacity of Tim-3 expressing T cells by examining 1) the ability of Tim-3+ CD8+ T cells to make perforin and 2) the direct ability of Tim-3+ CD8+ T cells to kill autologous HIV infected CD4+ target cells. Surprisingly, Tim-3+ CD8+ T cells maintain higher levels of perforin, which was mainly in a granule-associated (stored) conformation, as well as express high levels of T-bet. However, these cells were also defective in their ability to degranulate. Blocking the Tim-3 signalling pathway enhanced the cytotoxic capabilities of HIV specific CD8+ T cells from chronic progressors by increasing; a) their degranulation capacity, b) their ability to release perforin, c) their ability to target activated granzyme B to HIV antigen expressing CD4+ T cells and d) their ability to suppress HIV infection of CD4+ T cells. In this latter effect, blocking the Tim-3 pathway enhances the cytotoxcity of CD8+ T cells from chronic progressors to the level very close to that of T cells from viral controllers. Thus, the Tim-3 receptor, in addition to acting as a terminator for cytokine producing and proliferative functions of CTLs, can also down-regulate the CD8+ T cell cytotoxic function through inhibition of degranulation and perforin and granzyme secretion.
Highlights
The inability of T cell-mediated immune responses to control persistent viral infections, like human immunodeficiency virus-1 (HIV), has been correlated with the impairment in the ability of virus-specific T cells to produce cytokines, to proliferate and to survive [1,2]
It is possible that HIV antigen specific cells were enriched in the Tim-3 negative fraction, which could induce greater degranulation after peptide stimulation, when Peripheral Blood Mononuclear Cells (PBMC) were stained for HIV specific tetramers containing epitopes that were included in the peptide pool, we found the frequency of antigen specific cells tended to be more enriched in the Tim-3 positive population and as Tim-3 expression is stable or even increases to some extent after six hours of stimulation, it indicates an even distribution of HIV specific cells after stimulation (Figure S1)
As it has been previously shown in mice and human studies, Tim-3 positive T cells are dysfunctional in terms of cytokine production or proliferation [15,40,41,42,43,44,45]
Summary
The inability of T cell-mediated immune responses to control persistent viral infections, like human immunodeficiency virus-1 (HIV), has been correlated with the impairment in the ability of virus-specific T cells to produce cytokines, to proliferate and to survive [1,2]. We previously identified a novel population of ‘exhausted’ T cells in HIV infected individuals, which are marked by increased surface expression of the glycoprotein Tim-3. These cells, in contrast to programmed cell death -1 (PD-1) expressing cells, are relatively more deficient in effector cytokine production [15]. This transcription factor is required for proper perforin production and function in cytotoxic lymphocytes [16,17,18,19]
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