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Derya Unutmaz, M.D.

Assistant Professor
Researcher

Contact Information:

Vanderbilt University Medical Center
AA-5216 Medical Center North
Nashville, TN 37232-2363
615-322-1435

Research Specialty

The molecular machinery of T cell activation, differentiation, survival and its exploitation by HIV

Research Description

The first long-term focus is to understand how T cells compute and integrate the signals from the environment to initiate different effector functions or differentiation programs. The complex signaling machinery of T cells allows the immune system to have a flexible and vigorous response against different pathogen challenges.

The second and major focus of our lab is to understand how HIV exploits T cell activation and differentiation for its own survival. HIV has infected over 60 million and killed more than 20 million individuals worldwide. The infection continues to spread exponentially and kills 3 million people every year. Massive efforts over the past 20 years have failed to produce an effective and urgently needed vaccine.

Infection of T cells by HIV requires their activation. Therefore it is not surprising that the hallmarks of HIV infection are chronic immune activation and destruction of its targets, the CD4+ T cells. However, we still do not understand how HIV exploits chronic immune activation and how it causes severe developmental and homeostatic dysfunction of the immune system.

In the last several years we have made several very exciting discoveries that we believe have began to shed light into the highly complex immune pathogenesis of HIV infection. We initially demonstrated that HIV uses a Trojan horse like mechanism to be captured by the sentinels of the immune system, the dendritic cells, thus avoiding destruction, and possibly uses this mechanism to gain a foothold in the body during its transmission. We are now working to understand the mechanism by which HIV hijacks dendritic cells.

To understand how HIV causes severe immune homeostatic imbalance and dysfunction, we began to analyze T cell subsets in infected individuals. These studies led to the discovery that HIV preferentially infects Natural Killer T (NKT) cells and causes a profound depletion of these cells in infected individuals. Although the main function of NKT cells is not yet known, it is thought that they play a crucial immune amplification function during variety of infectious diseases. We have began in vivo experiments in monkeys in collaboration with our colleagues at Harvard to better understand the impact of NKT cell depletion during HIV infection and also continuing our efforts to understand how NKT cell depletion in HIV+ individuals affects disease progression.

Recently a subset of CD4+ T cells was identified as regulatory T cells (Tregs). The function of these cells is to suppress excessive T cell activation during unwanted immune responses such autoimmunity. We hypothesized that HIV targets and gradually depletes Tregs, thus removing the brakes of T cell activation, causing persistent immune activation. We have now discovered that Tregs are highly susceptible to HIV infection and are depleted during the late stages of the disease. Remarkably, we also found a highly significant correlation between the loss of Treg cells and the increase in activated CD4+ T cells in HIV infected individuals, as precisely predicted by our hypothesis.

How Tregs suppress activation of other T cells is not known. A major impediment in working with Tregs is that they are only about 2% of human T cells and are difficult to grow in vitro. In order to decode the function of Tregs and their role during HIV infection we have developed a method to genetically reprogram conventional T cells into Tregs by ectopically expressing a master transcription factor called FoxP3. The FoxP3-engineered T cells behave just like naturally occurring Treg cells and can be generated in unlimited numbers. This method has now paved the way for identifying mechanisms that mediate Treg cell suppressive function.

In summary, we would like to decode the complex sensory system of T cells that execute adaptable biological programs and to understand how HIV hacks into the "operating system" of these cells and exploits their "biocode" for its own survival.

Publications


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