REGULATORY T CELL MODULATION OF IMMUNITY TO MUCOSAL VIRAL INFECTIONS
Regulatory T cells are well known for their role in dampening the immune responses to self-antigens and thereby helping to prevent autoimmune disease. Additionally, recent work has highlighted the importance of regulatory T cells in immunity to infectious disease. Thus, the question arises as to how regulatory T cells can participate in both of these goals that are so important to human survival – preventing damaging immune responses to self while simultaneously permitting immune responses to be generated to fight foreign infectious agents. Previous studies have pointed to a role for regulatory T cells in limiting late immune responses to various infectious agents, thereby minimizing immune response-induced tissue damage while preventing or diminishing pathogen clearance. However, we recently demonstrated a novel and unexpected role for regulatory T cells in facilitating early immune responses to genital herpes simplex-2 (HSV-2) infection in orchestrating the timely trafficking of immune effector cells to the site of infection where they can fight infection. Therefore, this unexpected finding of an immune response-promoting function of regulatory T cells has subsequently led to several new lines of work that will be addressed in the lab.
Specifically, we will first address the role of regulatory T cells during the immune response to primary and secondary challenge with genital HSV-2 infection. This has important implications for vaccine design for sexually transmitted viruses, since how the population of regulatory T cells could change and perhaps impact the “memory” immune response that is generated subsequent to a primary antigenic challenge such as a vaccine is currently unknown. Secondly, we will extend our studies of the role of regulatory T cells during a second common mucosal infection that is considered to be a major public health threat- influenza virus infection. Thirdly, following up on work from our previous studies, we will characterize the mechanisms by which regulatory T cells modulate dendritic cell function during mucosal viral infections. Finally, we will determine if regulatory T cells must be antigen-specific in order to respond to genital HSV-2 infection. Results from these studies will help to reveal the roles of regulatory T cells during various types of mucosal viral infections at different mucosal surfaces of the body, as well as the different roles that regulatory T cells could play at various phases of the immune response to viruses. We expect that knowledge gained from this research program will assist in the generation of improved clinical interventions for mucosal viral infections, including vaccines. Our previously published work as well as recently generated and unpublished data in the lab suggests that regulatory T cells play several important roles in the immune response to viruses; thus, gaining an understanding of exactly what these cells do as well as where and when in the course of both a primary and secondary immune response is vital for designing future vaccines that will allow regulatory T cells to effectively assist in generating and maintaining protective immune responses.
Human immunodeficiency virus (HIV) infection poses a public health threat both in the U.S. as well as worldwide. A role for regulatory T cells, potent negative regulators of the adaptive and innate immune responses, is poorly understood in the case of viral infection in general and in HIV infection in particular. Therefore, in addition to the work described above, a continuation of the work I did during my postdoctoral studies, we also plan to extend our studies of regulatory T cells into the role(s) they play during HIV infection and vaccine responses in collaboration with Dr. Julie McElrath.
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