autoimmune disorder, cancer, healthinnovations, immune cell, immunology, opensource, PSGL-1, T cell

Study identifies a new regulator of immune responses.

T cells are the immune cells responsible for recognizing and destroying specific invaders, such as viruses, bacteria, or cancer. Their activity is highly tunable, with signals from other cells adjusting T cell responses to counteract the invasion. However, sometimes those responses fall short, as in chronic viral infections and cancers that thwart immune responses by inducing T cell dysfunction.  Now, a study led by scientists at the Sanford Burnham Prebys Medical Discovery Institute (SBP) identifies a new regulator of immune responses which sheds new light on why T cells fail to clear chronic infections or eliminate tumours. The team state that their findings open the door for a new approach to modulating T cell responses in many clinical settings, including infections, autoimmune diseases, and cancers that are unresponsive to currently available therapies.  The opensource study is published in the journal Immunity.

Previous studies show that the recent emergence of drugs that block immune checkpoints has provided a new, improved approach to treating certain cancers such as lung cancer and melanoma. Immune checkpoints act as brakes for T cells, restraining the immune system from self-attack and preventing autoimmune diseases. Inhibitors of checkpoints remove these brakes, and unleash the immune system to tackle these cancers, in some cases extending survival by years.  The current study shows that a protein on the surface of T cell, known as P-selectin glycoprotein ligand-1 (PSGL-1), increases the level of immune checkpoints to allow T cell inhibition; when PSGL-1 is missing, the brakes are off, and T cells remain active longer than normal.

The current study utilised a mouse-model engineered to lack PSGL-1. Results show that these mice completely eradicated lymphocytic choriomeningitis virus (LCMV) infections, which normally last months.  The lab explain that total clearance of LCMV is rare, so once it was observed that total clearance had indeed happened, it was evident that PSGL-1 was crucial for limiting immune responses.

The group then looked at whether this lack of an immune brake would impact cancer by injecting the same mice with melanoma cells. Results show that tumours grew much slower than they do in normal mice, showing PSGL-1 regulates T cell responses in general.

The lab hypothesize that blocking PSGL-1 may enhance the immune response to cancer and chronic viral infections such as hepatitis. They go on to add that, in contrast, activating PSGL-1 may be a way to inhibit immune responses that could potentially be used to treat autoimmune diseases, such as rheumatoid arthritis, psoriasis, multiple sclerosis and lupus.

The team surmise that their findings show that PSGL-1 acts as a negative regulator of T cell function.  They go on to add that PSGL-1 has the broad capacity to dampen T cell signals and promote the exhaustion of T cells in viral and tumour mouse models.  For the future, the researchers state that PSGL-1 inhibitors could be another tool in the arsenal against cancer, and benefit patients who don’t respond to current checkpoint inhibitors.

Source: Sanford Burnham Prebys Medical Discovery Institute (SBP) 

 

Chronic viruses and cancers thwart immune responses in humans by inducing T cell dysfunction. Using a murine chronic virus that models human infections, we investigated the function of the adhesion molecule, P-selectin glycoprotein ligand-1 (PSGL-1), that is upregulated on responding T cells. PSGL-1-deficient mice cleared the virus due to increased intrinsic survival of multifunctional effector T cells that had downregulated PD-1 as well as other inhibitory receptors. Notably, this response resulted in CD4+-T-cell-dependent immunopathology. Mechanistically, PSGL-1 ligation on exhausted CD8+ T cells inhibited T cell receptor (TCR) and interleukin-2 (IL-2) signaling and upregulated PD-1, leading to diminished survival with TCR stimulation. In models of melanoma cancer in which T cell dysfunction occurs, PSGL-1 deficiency led to PD-1 downregulation, improved T cell responses, and tumor control. Thus, PSGL-1 plays a fundamental role in balancing viral control and immunopathology and also functions to regulate T cell responses in the tumor microenvironment. PSGL-1 Is an Immune Checkpoint Regulator that Promotes T Cell Exhaustion. Bradley et al 2016.
Chronic viruses and cancers thwart immune responses in humans by inducing T cell dysfunction. Using a murine chronic virus that models human infections, we investigated the function of the adhesion molecule, P-selectin glycoprotein ligand-1 (PSGL-1), that is upregulated on responding T cells. PSGL-1-deficient mice cleared the virus due to increased intrinsic survival of multifunctional effector T cells that had downregulated PD-1 as well as other inhibitory receptors. Notably, this response resulted in CD4+-T-cell-dependent immunopathology. Mechanistically, PSGL-1 ligation on exhausted CD8+ T cells inhibited T cell receptor (TCR) and interleukin-2 (IL-2) signaling and upregulated PD-1, leading to diminished survival with TCR stimulation. In models of melanoma cancer in which T cell dysfunction occurs, PSGL-1 deficiency led to PD-1 downregulation, improved T cell responses, and tumor control. Thus, PSGL-1 plays a fundamental role in balancing viral control and immunopathology and also functions to regulate T cell responses in the tumor microenvironment. PSGL-1 Is an Immune Checkpoint Regulator that Promotes T Cell Exhaustion. Bradley et al 2016.

 

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