Cytotoxic T lymphocytes (CTL) can protect against HeCrpes simplex virus type 1 (HSV-1) infections by destroying infected cells (cytotoxicity) or by inhibiting virus replication through the elaboration of antiviral cytokines. Studies during the current funding period established that both the host and the virus have developed tissue-specific mechanisms to regulate CTL function. We will now further define these regulatory mechanisms.
Specific aims 1 and 2 will investigate a novel regulatory circuit in the cornea that controls CTL functions. Corneal fibroblasts, upon exposure to a soluble factor from HSV-1 infected normal spleen cells, strongly induce the production of the antiviral cytokine interferon (IFN)-gamma, while actively inhibiting their proliferation and differentiation into cytotoxic effector cells.
Specific aim 1 is to define the mechanism by which corneal fibroblasts inhibit CTL precursor proliferation and acquisition of cytotoxic function. We will determine the effect of corneal fibroblasts: 1) on early and late T cell receptor (TCR) signaling events in CTL precursors; 2) on the capacity on CTL precursors to produce the lytic granules that mediate target cell destruction, and their ability to exocytose these granules upon TCR stimulation; and 3) on the ability of the CTL to bind to the target cells and to express the adhesion molecules that facilitate this binding. Studies in specific aim 2 will determine the source and identity of the inhibitory factor that regulates CTL precursor activation by corneal fibroblasts.
Specific aim 3 is to further our studies of HSV immune evasion mechanisms. We have established that the HSV-1 US12 gene product, ICP47 can augment HSV-1 neurovirulence in mice by inhibiting a protective CTL response. We will now pursue our suggestive evidence that the closely linked US11 gene product can serve a similar function. These studies will utilize HSV-1 US11 deletion mutants, US11/US12 double deletion mutants, and their revertants. We will employ both in vivo and in vitro studies to investigate the effect of the US11 and US12 gene products on CTL control of HSV-1 replication in the trigeminal ganglia and brains of infected mice. By providing a better understanding of the complex interaction among HSV-1, specific host tissues, and CTL we hope to devise new strategies to provide optimal host protection, with minimal immunopathology.
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