Thomas J. Braciale, MD, PhD
T lymphocyte activation and in vivo trafficking in infection and autoimmunity
Research Interests: Antiviral Immunity, Regulation of T-lymphocyte activation/differentiation, Control of T-lymphocyte function by viral gene products.
Cells of the Immune System play a central role in eliminating infectious agents from the body. One of these cell types, the T-lymphocyte, plays an important role in eliminating viruses and virus-infected cells. T-lymphocytes carry out this antiviral activity by producing "effector molecules" after encountering viral antigen. These T-lymphocyte effector molecules not only act to eliminate virus-infected cells, but these same effector molecules are also believed to produce damage to normal cells and tissues during infection. They now know that much of the symptoms and injury produced during virus infection is not due to the virus per se, but due to the host response (including the T-lymphocyte response) to the virus.
The Braciale laboratory is interested in how T-lymphocytes respond to infection with two important human viruses: Type A Influenza Virus and Respiratory Syncytial Virus (RSV). Their research focuses on several areas. One area of research is to define which T-lymphocyte effector molecules are involved in clearing virus from the site of infection, and which effector molecules lead to injury. They analyze this process by examining the expression of specific cytokine and chemokine genes during experimental Influenza and RSV infection of mice. One way that they modify the outcome of infection is by transferring T-lymphocytes specific for the virus into infected animals. They have previously shown that, by adoptively transferring virus-specific T-cells, they can protect infected recipient mice from lethal infection. Using transgenic and gene knock-out technology to over-express or delete the genes encoding specific effector molecules in the transferred T-cells, they are determining how the expression of particular cytokines or chemokines in the transferred T-lymphocytes affects the outcome of infection and results in injury to normal cells in the infected lungs.
A second important area of research is aimed at analyzing the process by which T-lymphocytes directed to these viruses first recognize viral antigen in the body, and then activate and differentiate into effector cells which function to eliminate the virus and virus infected cells at the site of infection. In the case of influenza and RSV, the major site of infection of the body is the respiratory tract. An important interface between the body's immune system and virus/virus-infected cells in the lungs are antigen presenting cells that line the respiratory tract (i.e. Respiratory Dendritic cells or RDC). RDC are believed to capture viral antigen and migrate into regional draining lymph nodes, where they present that viral antigen to T-lymphocytes. They are interested in the nature and form of the antigen presented by RDCs to T-cells during respiratory viral infection. They are also interested in understanding the impact of the expression of certain viral genes on the ability of RDC to stimulate T-cell activation and differentiation. They currently have considerable evidence to suggest that the initial inoculum dose of virus used to infect experimental animals in vivo profoundly affects the ability of RDC to stimulate T-cell differentiation in the infected lungs.
The third area of investigation involves understanding how the structure of a viral protein or a peptide epitope (fragment) derived from the viral protein which engages the T-cell antigen receptor directs the type of effector molecules produced by the activated T-cell. In one instance, they have demonstrated that a specific fragment of the RSV-G glycoprotein triggers T-lymphocytes to preferentially produce the cytokine IL-5. Expression of this effector molecule is associated with the development of allergic (asthma-like) responses. These studies will help us understand the link between RSV infection and asthma development in children. In related studies in the RSV model they have obtained evidence that the terminal differentiation of activated T-cells into "effector" cells in the lungs during RSV infection is inhibited by expression of one or more RSV gene products. They are currently working to identify the suppressive gene products encoded by RSV, and to determine their mechanism of action in suppressing T-cell activation/differentiation.