T
cells play a central role in adaptive immunity. Once they are activated, they can rapidly divide and differentiate to set in motion a potentially devastating cascade of effector responses. This is great if the target of their activity is a pathogen ... but if it turns out to be a self antigen, these responses can lead to autoimmunity. So, the system has evolved an elaborate series of checks and balances to ensure that a T cell response is activated and maintained only where it is needed and useful. We are interested in understanding the cellular logic that the adaptive immune system uses to make these discriminatory decisions.
Project:
T
he ability of T cells to very specifically recognize any given pathogen is structurally enabled by the T cell receptor (TCR). TCRs are generated in the body by a random genetic recombination process and the T cell has no way of knowing whether the small peptide (<15 amino acids) that this TCR binds to is from a self-antigen or a “foreign” one. Although the thymus tries to clear out many self reactive ones, using a process known as negative selection, many potentially self-reactive T cells still populate our body.
Over the years, several mechanisms that help the immune system to restrain such self-reactive T cells from being fully activated and armed have been revealed. These include the requirement for activated dendritic cells to trigger naïve T cells (the two-signal model), the presence of specialized subsets of immune-dampening cells (regulatory T cells), the expression of protective molecules on healthy self-cells (FasL, TGFb etc.) etc. We are interested in a process known as “T cell tuning” - a quantitative cell-autonomous mechanism - i.e., the software coding for this process and the hardware required for it is all within the same T cell.
Tuning was originally proposed as a mechanism of peripheral T cell regulation by Dr. Zvi Grossmann and Dr. William E Paul in a seminal article in 1992. ( Click for a recent review of the topic). The basic idea is that T cells have the ability to dynamically adjust their ability to respond based on the duration for which they keep sensing their antigen. So, when T cells are activated by chronic antigens - e.g. most self antigens or those from pathogens which they cant clear from the system, a negative feedback inside the T cell, shuts down continued activation (see animation on the right).
In the Figure above, the T cell on the left is stimulated by an antigen from an acute infection. Over time (see progress of timeline on top of figure), the activation of the T cell and the resulting response leads to clearance of the pathogen. Since this stops the supply of antigen to the DCs, the T cell response can be shut down. However the T cell on the right is activated by a chronic antigen (e.g. antigens from self tissues, tumors, persistent viruses etc.). How does this response terminate ? We and others have shown that tuning plays a critical role in this context. We are interested in understanding the molecular mechanisms by which the tuning machinery operates. This will allow us to develop new treatments for tumors, chronic infections as well as autoimmunity.
Over the years, several mechanisms that help the immune system to restrain such self-reactive T cells from being fully activated and armed have been revealed. These include the requirement for activated dendritic cells to trigger naïve T cells (the two-signal model), the presence of specialized subsets of immune-dampening cells (regulatory T cells), the expression of protective molecules on healthy self-cells (FasL, TGFb etc.) etc. We are interested in a process known as “T cell tuning” - a quantitative cell-autonomous mechanism - i.e., the software coding for this process and the hardware required for it is all within the same T cell.
Tuning was originally proposed as a mechanism of peripheral T cell regulation by Dr. Zvi Grossmann and Dr. William E Paul in a seminal article in 1992. ( Click for a recent review of the topic). The basic idea is that T cells have the ability to dynamically adjust their ability to respond based on the duration for which they keep sensing their antigen. So, when T cells are activated by chronic antigens - e.g. most self antigens or those from pathogens which they cant clear from the system, a negative feedback inside the T cell, shuts down continued activation (see animation on the right).
In the Figure above, the T cell on the left is stimulated by an antigen from an acute infection. Over time (see progress of timeline on top of figure), the activation of the T cell and the resulting response leads to clearance of the pathogen. Since this stops the supply of antigen to the DCs, the T cell response can be shut down. However the T cell on the right is activated by a chronic antigen (e.g. antigens from self tissues, tumors, persistent viruses etc.). How does this response terminate ? We and others have shown that tuning plays a critical role in this context. We are interested in understanding the molecular mechanisms by which the tuning machinery operates. This will allow us to develop new treatments for tumors, chronic infections as well as autoimmunity.