Current concepts of the establishment and maintenance of long-term T cell memory propose that memory T cells are derived from a small; surviving subpopulation of effector T cells. Using a model of cutaneous HSV-1 infection in C57BL/6 mice, we have found that the ability to control infection is highly dependent upon the presence of HSV-1-specific CD4+ and CD8+ T cells, with the principal role being played by CD8+ T cells expressing cytolytic function and able to synthesize interferon-gamma (IFN-gamma). The ability to express CTL function was intimately linked with the increased expression of the IL-2 receptor alpha-chain, CD25. This observation lead to the conclusion that expression of high levels of CD25 was mandatory for the expression of HSV-specific CTL activity. However, a subpopulation of CD8+ T cells, present both within the draining regional lymph node and within the spleen during the early phase of the response to infection, has been identified. These cells synthesize IFN-gamma following antigenic stimulation in vitro without expressing elevated levels of CD25. In all other aspects, these CD8+ T cells have all of the characteristics of activated cells, suggesting that they may represent a population of effector cells able to synthesize only cytokines rather than express perforin-dependent CTL function, or may be the direct progenitors of memory CD8+ T cells. The hypothesis to be addressed is that this CD8+ T cell subpopulation represents a lineage of cells able to enter directly into the memory pool without proceeding through the full activation program to attain CTL function.
Five specific aims will be studied.
In Aim 1, the acquisition of in vivo cytolytic and cytokine synthetic functions of the CD8+ T cell subpopulations will be analyzed in detail throughout the course of the initial response to infection. Also, defined CD8+ T cells will be transferred to recipient animals, and the functions of the progeny determined.
In Aim 2, the ability of this subpopulation to contribute to long-term memory will be assessed by adoptive transfer into appropriate recipient mice. This ability will be compared directly with """"""""authentic"""""""" memory CD8+ T cells obtained from long-term convalescent mice.
Aim 3 will address the activation status and function of the distinct CD8+ T cell subpopulations using a newly developed transgenic model, through the analysis of important signaling mediators, and the ability of the cells to persist as determined by measuring the percentage of apoptotic cells and the expression of anti-apoptotic molecules.
Aim 4 will determine the phenotypic characteristics of the distinct CD8+ T cells to understand the molecular basis for differences in the migratory patterns in vivo.
Aim 5 will address the role of different cytokine species in the clonal expansion and differentiation of the distinct CD8+ T cells, with focus given to the role of cytokines responsible for proliferation and differentiation. Overall, the proposal will determine whether the CD8+ CD25neg T cells contribute to memory, are a distinct subpopulation of effector cells with unique characteristics, or a developmental dead end. Greater insight into CD8 T cell biology will result from these studies.
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| Kassim, Sadik H; Rajasagi, Naveen K; Ritz, Barry W et al. (2009) Dendritic cells are required for optimal activation of natural killer functions following primary infection with herpes simplex virus type 1. J Virol 83:3175-86 |
| Rajasagi, Naveen K; Kassim, Sadik H; Kollias, Christina M et al. (2009) CD4+ T cells are required for the priming of CD8+ T cells following infection with herpes simplex virus type 1. J Virol 83:5256-68 |
| Kassim, Sadik H; Rajasagi, Naveen K; Zhao, Xiangyi et al. (2006) In vivo ablation of CD11c-positive dendritic cells increases susceptibility to herpes simplex virus type 1 infection and diminishes NK and T-cell responses. J Virol 80:3985-93 |
