autoimmune disease, healthinnovations, immune response, immune system, immunology, immunotherapy, inflammation, inflammatory response, Interleukin, opensource

New T-cell regulation discovery set to rewrite immunology text books.

To be activated, T cells must first recognize an antigen, receive appropriate costimulatory signals, and then encounter inflammatory cytokines to expand the immune response. This immune response has been harnessed via immunotherapies, treatment that uses certain parts of a person’s immune system to fight diseases such as cancer.  It has been somewhat of a mystery as to how some of these immunotherapies have been shown to hamper overall immunity.

Now researchers from UC Davis state that, in a discovery that is likely to rewrite immunology text books, they have found that sending the third signal early, as is done with some immunotherapies, could actually hamper overall immunity.  The new study found that early exposure to inflammatory cytokines, such as interleukin 2, can paralyze CD4 T cells, immune components that help orchestrate the body’s response to pathogens and other invaders.  The opensource study is published in the journal Immunity.

Previous studies show that these stimulatory immunotherapies are designed to activate the immune system, however, considering how T cells respond, that approach could damage a patient’s ability to fight off pathogens. While immunotherapies might fight cancer, they may also open the door to opportunistic infections.  This is because there’s a three-signal process to activate T cells of which each component is essential for proper activation.  However, the group note that past research hadn’t really looked at what happens if they are delivered out of sequence. They go on to add that if the third signal, cytokines, is given prematurely, it basically paralyzes CD4 T cells.

The current study showed this in mice which, after receiving systemic immunotherapy, had trouble mounting a primary T-cell response. The data findings were also validated in samples from patients receiving high-dose interleukin 2 therapy to treat metastatic melanoma.  The team explain that this mechanism may act as a firewall, shutting down the immune response before it gets out of hand. They go on to add that from a clinical standpoint, this discovery could lead to more effective cancer immunotherapies, better drugs for autoimmune conditions and new ways to expedite recovery from sepsis.

In addition to illuminating how T cells respond to cancer immunotherapy, the current study also provides insights into autoimmune disorders. The researchers believe this CD4 paralysis mechanism could play a role in preventing autoimmunity, a hypothesis they supported by testing immunotherapy in a multiple sclerosis model.

The results showed that by shutting down CD4 T cells, immune stimulation prevented an autoimmune response.  The lab note that this offers the potential to paralyze the immune system to prevent autoimmunity or modulate it to accept transplanted cells or entire organs. They go on to add that CD4 paralysis may also be co-opted by pathogens, such as HIV, which could use this chronic inflammation response to disable the immune system.

The team surmise that this really highlights the importance of CD4 T cells, the fact that they’re regulated and suppressed means they are definitely the orchestrators the global community need to take into account. They go on to conclude that researchers may need to be very careful because immunotherapy could be generating both short-term gain and long-term loss.

For the future the researcher’s next step is to continue this research in older mice. They explain that age can bring a measurable loss in immune function, and inflammation may play a role in that process.

Source:  University of California – Davis Health System

 

Primary T cell activation involves the integration of three distinct signals delivered in sequence: (1) antigen recognition, (2) costimulation, and (3) cytokine-mediated differentiation and expansion. Strong immunostimulatory events such as immunotherapy or infection induce profound cytokine release causing “bystander” T cell activation, thereby increasing the potential for autoreactivity and need for control. We show that during strong stimulation, a profound suppression of primary CD4+ T-cell-mediated immune responses ensued and was observed across preclinical models and patients undergoing high-dose interleukin-2 (IL-2) therapy. This suppression targeted naive CD4+ but not CD8+ T cells and was mediated through transient suppressor of cytokine signaling-3 (SOCS3) inhibition of the STAT5b transcription factor signaling pathway. These events resulted in complete paralysis of primary CD4+ T cell activation, affecting memory generation and induction of autoimmunity as well as impaired viral clearance. These data highlight the critical regulation of naive CD4+ T cells during inflammatory conditions. Out-of-Sequence Signal 3 Paralyzes Primary CD4+ T-Cell-Dependent Immunity. Murphy et al 2015.
Primary T cell activation involves the integration of three distinct signals delivered in sequence: (1) antigen recognition, (2) costimulation, and (3) cytokine-mediated differentiation and expansion. Strong immunostimulatory events such as immunotherapy or infection induce profound cytokine release causing “bystander” T cell activation, thereby increasing the potential for autoreactivity and need for control. We show that during strong stimulation, a profound suppression of primary CD4+ T-cell-mediated immune responses ensued and was observed across preclinical models and patients undergoing high-dose interleukin-2 (IL-2) therapy. This suppression targeted naive CD4+ but not CD8+ T cells and was mediated through transient suppressor of cytokine signaling-3 (SOCS3) inhibition of the STAT5b transcription factor signaling pathway. These events resulted in complete paralysis of primary CD4+ T cell activation, affecting memory generation and induction of autoimmunity as well as impaired viral clearance. These data highlight the critical regulation of naive CD4+ T cells during inflammatory conditions. Out-of-Sequence Signal 3 Paralyzes Primary CD4+ T-Cell-Dependent Immunity. Murphy et al 2015.

 

Leave a Reply

This site uses Akismet to reduce spam. Learn how your comment data is processed.