Cornea lymphatics drive the CD8⁺ T‐cell response to herpes simplex virus‐1

Abstract

Herpes simplex virus type 1 (HSV-1) infection of the cornea induces vascular endothelial growth factor (VEGF)-A-dependent lymphangiogenesis. However, the extent to which HSV-1-induced corneal lymphangiogenesis impacts the adaptive immune response has not been characterized. Here, we used floxed VEGF-A mice to study the importance of newly created corneal lymphatic vessels in the host adaptive immune response to infection. Whereas the mice infected with the parental virus (strain SC16) exhibited robust corneal lymphangiogenesis, mice that received the recombinant virus (SC16 ICP0-Cre) that expresses Cre recombinase under the control of infected cell protein 0 (ICP0), an HSV-1 immediate early gene, showed a significant reduction in lymphangiogenesis. There was no difference in virus recovered from the cornea of mice infected with SC16 vs SC16 ICP0-Cre. However, viral loads were significantly elevated in the trigeminal ganglia (TG) of mice with reduced corneal lymphangiogenesis. The increase in viral titer correlated with a significant loss of HSV-1-specific CD8+ T cells that traffic to the TG of mice infected with the recombinant virus. Intrastromal delivery of size exclusion dye (FITC-dextran) revealed a time-dependent defect in the ability of the lymphatic vessels in SC16 ICP0-Cre infected mice to transport soluble antigen from the cornea to the draining lymph nodes. We interpret these results to suggest that the newly created lymphatic vessels in the cornea driven by HSV-1 infection are critical in the delivery of soluble viral antigen to the draining lymph node and subsequent development of the CD8+ T cell response to HSV-1.

Lymphatic Vessels Balance Viral Dissemination and Immune Activation following Cutaneous Viral Infection

“…Persistent lymphatic vessel hyperplasia results following chronic respiratory tract infection with mycoplasma pulmonis, resulting in bronchial lymphedema, and airflow obstruction (Baluk et al, 2005; Yao et al, 2010), and sustained inflammation following Yersinia pseudotuberculosis infection induces lymphatic leakage, insufficient dendritic cell (DC) trafficking, and persistently compromised canonical mucosal immunity (Fonseca et al, 2015). Furthermore, corneal herpes simplex 1 (HSV-1) infection induces lymphangiogenesis driven by the expression of vascular endothelial growth factor A (VEGF-A) from infected corneal epithelial cells (Wuest and Carr, 2010), leading to enhanced antigen drainage and CD8 + T cell immunity (Gurung et al, 2016). We therefore hypothesized, that in the context of active viral replication in non-lymphoid tissue, contextual cues influence regional lymphatic vessel function, downstream immune induction, and host viral defense.…”

Lymphangiogenesis: a new player in herpes simplex virus 1‐triggered T‐cell response

“…In addition, studies from other researchers have shown that antigen‐specific CD8 + T cells are critical in preventing HSV‐1 lytic cycle activation in the trigeminal ganglia (TG), the anatomical site where the virus establishes a latent infection for the lifetime of the host 3 . Now in the current study, 1 Gurung et al 1 have further demonstrated that corneal LG is indispensable to evoke a CD8 + T‐cell‐mediated immune response against the HSV‐1 infection. The authors employed an ingenuous method to specifically suppress corneal LG upon HSV‐1 infection.…”

“…In a new study by Gurung et al 1 published in this issue of Immunology and Cell Biology , the authors described how corneal lymphangiogenesis (LG) can influence the activation of the adaptive immune system against herpes simplex virus type 1 (HSV‐1) infection (Figure 1). Previous studies from these authors have investigated the role of HSV‐1 infection in triggering VEGF‐A‐dependent neovascularization in mouse cornea 2 .…”

Potential lymphangiogenesis therapies: Learning from current antiangiogenesis therapies—A review

“…This interaction may be fortified by LYVE‐1, as glycosylated LYVE‐1 binds FGF2 tightly, and in fact, soluble LYVE‐1 inhibits FGF2‐mediated lymphangiogenesis . However, inhibition of FGF2 in targeted therapies must be executed carefully to avoid possible toxicities; for example, FGF2 is involved in neurogenesis and its inhibition may impair nerve regeneration . Furthermore, FGF2 and VEGF‐C were shown to work synergistically to promote tumor growth and metastasis to the lung via blood vessels and to sentinel lymph nodes via lymphatic vessels in a mouse model of fibrosarcoma .…”

“…193 However, inhibition of FGF2 in targeted therapies must be executed carefully to avoid possible toxicities; for example, FGF2 is involved in neurogenesis and its inhibition may impair nerve regeneration. 80,194 Furthermore, FGF2 and VEGF-C were shown to work synergistically to promote tumor growth and metastasis to the lung via blood vessels and to sentinel lymph nodes via lymphatic vessels in a mouse model of fibrosarcoma. 192 Together, these studies support the advantage of combination therapies that inhibit both FGFR and VEGFR-3 signaling to therapeutically target pathologic lymphangiogenesis.…”