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Fatemeh Navid, Chengrong Yu, Ivy Dambuza, Gregory M. Frank, Charles E. Egwuagu, Immunology; STAT3/SOCS3 axis modulates CD8-mediated host immunity against HSV-1. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5989.
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© ARVO (1962-2015); The Authors (2016-present)
Herpes Simplex Virus (HSV-1) is the most common cause of cornea-derived blindness in developed nations and is a major global public health problem. Cytokines have profound influence on the activation, development and expansion of T cells that confer protection against HSV-1 and other infectious agents. The JAK/STAT pathway regulates the intensity and duration of cytokine signals and is in turn under feedback regulation by suppressors of cytokine signaling (SOCS) proteins. Recent reports indicate that STAT3 inhibits T-helper cell proliferation and IL-2 production while SOCS3 inhibits Treg proliferation and suppressive functions. In this study we investigated whether STAT3 and SOCS3 contribute to the regulation of cell-mediated immunity against HSV-1 infection.
We have generated mice with conditional deletion of STAT3 (STAT3KO) or SOCS3 (SOCS3KO) in CD4 and CD8 T cells and infected them by intraperitoneal injection with the HSV-1 strain REpICP0-EGFP (Journal of Virology, 79:10339-10347, 2005). Viremia was measured at different time points post immunization (p.i.) by plaque assay. Splenocytes and lymph node cells were analyzed for the expansion of HSV-1-specific CD8 cells using an anti HSV-1 gB Tetramer-PE antibody and [3H] Thymidine incorpoaration assay. T cell immunophenotype was characterized by FACS analysis and cytokine secretion was analyzed by the intracellular cytokine assay.
In comparison to WT mice, HSV-1-specific CD8 T cells were significantly elevated in STAT3KO mice at the peak of the infection while loss of SOCS3 in T cells correlated with substantial decrease in HSV-1-specific CD8 T cell numbers in the SOCS3KO mice.
Our data indicate that STAT3 and SOCS3 may have diametrically opposite effects on cell-mediated immune response to HSV-1 infection, with STAT3 inhibiting the expansion of HSV-1-specific CD8 T cells. As SOCS3 antagonizes Treg expansion and suppressive activities, our data suggests that it may promote the expansion of HSV-1-specific CD8 cells by restraining the inhibitory effects of Tregs. Taken together, targeting STAT3/SOCS3 axis might be a beneficial therapeutic strategy to modulate the CD8-mediated host immunity against HSV-1.
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