Program Director/Principal Investigator (Last, First, Middle): Marzo, Amanda, Lee Abstract/Summary. The majority of viral infections in the FRT are established through transmission across mucosal surfaces that line the genital tract. However much of what we currently know about the generation and function of memory CD8 T cells is through the study of CD8 T cells found in the blood and secondary lymphoid tissues. Despite the fact that memory CD8 T cells in secondary lymphoid tissues and mucosal tissues originate from the same population of nave precursors, they are functionally distinct. In the mucosa CD8 T cells express higher levels of Granzyme B, CD69, and express markers that confer them with the ability to traffic to and persist in specific sites. Successful control of infections that occur in the FRT, such as HSV-2, are thought to be associated with the presence of sustained tissue resident memory CD8 T cells that reside in the draining lymph nodes of the genital tract and the vaginal mucosal tissues. The proposed research intends to determine if we can increase HSV-2 specific effector memory CD8 T cells in the FRT by regulating the level of mTOR signaling using rapamycin. This will be addressed in aims 1 and 2.
Specific Aim 1 will determine to what extent rapamycin modulates the generation of tissue resident HSV-2-specific effector memory CD8 T cells in the FRT.
In Specific Aim 2 will determine if HSV-2-specific CD8 T cells in the FRT can be enhanced by IL-15 therapy. This will be achieved by establishing if IL-15 administration can reprogram memory CD8 T cells in other tissues to traffic to the FRT and if the age of the memory CD8 T cell impacts their migratory capacity in response to IL- 15. The proposed research is significant, because it will provide insight into our understanding of the mechanisms and signals involved in generating HSV-2-specific effector memory CD8 T cells in the FRT provide opportunities to exploit them in strategies to enhance cellular immunity in the FRT that would ultimately protect women against HSV-2. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page
Marzo, Amanda, Lee Immunological memory is the basis for long-lasting protective immunity. An important aspect of this line of defense is the class of immune cells known as CD8T lymphocytes. These cells are crucial for both clearance of viruses and limiting the growth of virally infected cells. The CD8 T cell response to virus results in the formation of a memory population of cells, which serves as a protective barrier against future insults by the same virus. This proposal is focused on determining whether by manipulating the mTOR pathway or administration of the cytokine IL-15 we can boost the number of functional HSV-specific memory CD8 T cells in the Female Reproductive Tract and prevent establishment and provide protection from further HSV infections. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page
| Sowell, Ryan T; Goldufsky, Josef W; Rogozinska, Magdalena et al. (2017) IL-15 Complexes Induce Migration of Resting Memory CD8 T Cells into Mucosal Tissues. J Immunol 199:2536-2546 |
