HSV-1 Targets Lymphatic Vessels in the Eye and Draining Lymph Node of Mice Leading to Edema in the Absence of a Functional Type I Interferon Response

Herpes simplex virus type-1 (HSV-1) induces new lymphatic vessel growth (lymphangiogenesis) in the cornea via expression of vascular endothelial growth factor by virally infected epithelial cells. Here, we extend this observation to demonstrate the selective targeting of corneal lymphatics by HSV-1 in the absence of functional type I interferon (IFN) pathway. Specifically, we examined the impact of HSV-1 replication on angiogenesis using type I IFN receptor deficient (CD118−/−) mice. HSV-1-induced lymphatic and blood vessel growth into the cornea proper was time-dependent in immunocompetent animals. In contrast, there was an initial robust growth of lymphatic vessels into the cornea of HSV-1-infected CD118−/−mice, but such vessels disappeared by day 5 postinfection. The loss was selective as blood vessel integrity remained intact. Magnetic resonance imaging and confocal microscopy analysis of the draining lymph nodes of CD118−/− mice revealed extensive edema and loss of lymphatics compared with wild-type mice. In addition to a loss of lymphatic vessels in CD118−/− mice, HSV-1 infection resulted in epithelial thinning associated with geographic lesions and edema within the cornea, which is consistent with a loss of lymphatic vasculature. These results underscore the key role functional type I IFN pathway plays in the maintenance of structural integrity within the cornea in addition to the anti-viral characteristics often ascribed to the type I IFN cytokine family. Herpes simplex virus type-1 (HSV-1) induces new lymphatic vessel growth (lymphangiogenesis) in the cornea via expression of vascular endothelial growth factor by virally infected epithelial cells. Here, we extend this observation to demonstrate the selective targeting of corneal lymphatics by HSV-1 in the absence of functional type I interferon (IFN) pathway. Specifically, we examined the impact of HSV-1 replication on angiogenesis using type I IFN receptor deficient (CD118−/−) mice. HSV-1-induced lymphatic and blood vessel growth into the cornea proper was time-dependent in immunocompetent animals. In contrast, there was an initial robust growth of lymphatic vessels into the cornea of HSV-1-infected CD118−/−mice, but such vessels disappeared by day 5 postinfection. The loss was selective as blood vessel integrity remained intact. Magnetic resonance imaging and confocal microscopy analysis of the draining lymph nodes of CD118−/− mice revealed extensive edema and loss of lymphatics compared with wild-type mice. In addition to a loss of lymphatic vessels in CD118−/− mice, HSV-1 infection resulted in epithelial thinning associated with geographic lesions and edema within the cornea, which is consistent with a loss of lymphatic vasculature. These results underscore the key role functional type I IFN pathway plays in the maintenance of structural integrity within the cornea in addition to the anti-viral characteristics often ascribed to the type I IFN cytokine family. The primary function of the lymphatic system is to drain fluid and macromolecules from peripheral tissue and return them to the blood circulation to maintain appropriate peripheral tissue pressure.1Karpanen T. Alitalo K. Molecular biology and pathology of lymphangiogenesis.Annu Rev Pathol. 2008; 3: 367-397Crossref PubMed Scopus (285) Google Scholar Antigen, antigen-presenting cells, and soluble factors drain from the site of inflammation to the regional lymph nodes (LNs).1Karpanen T. Alitalo K. Molecular biology and pathology of lymphangiogenesis.Annu Rev Pathol. 2008; 3: 367-397Crossref PubMed Scopus (285) Google Scholar This process is due to structural differences between blood and lymphatic capillaries. The endothelial cells of blood capillaries form tight junctions are surrounded by a basement membrane and by vascular smooth muscle cells,1Karpanen T. Alitalo K. Molecular biology and pathology of lymphangiogenesis.Annu Rev Pathol. 2008; 3: 367-397Crossref PubMed Scopus (285) Google Scholar whereas lymphatic capillaries are composed of a single layer of endothelial cells connected loosely by button-like junctions that facilitate the uptake of CCR7+ immune cells via CCL21 expression by lymphatic endothelial cells (LECs).2Shields J.D. Lymphatics: at the interface of immunity, tolerance, and tumor metastasis.Microcirculation. 2011; 18: 517-531Crossref PubMed Scopus (14) Google Scholar Therefore, the lymphatic system plays a crucial role bridging the innate immune response at the site of inflammation to the generation of an adaptive immune response in the draining LN. However, under pathological conditions lymphangiogenesis or the impairment of proper lymphatic drainage can contribute to tumor metastasis, chronic inflammation, or lymphedema. Blood and lymphatic vessels are critical for tissue maintenance; however, certain tissues, such as the central cornea, are avascular. The absence of blood and lymphatic vessels in the cornea is necessary for visual acuity. However, hemangiogenesis and lymphangiogenesis can occur after inflammation or transplantation. With the identification of novel lymphatic vessel markers [lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), prospero homeobox 1 (Prox1), and podoplanin], corneal lymphangiogenesis has been investigated using wound healing and corneal transplantation models. In these studies, corneal lymphangiogenesis was associated with hemangiogenesis contributed by inflammatory cells through vascular endothelial growth factor (VEGF)-C/VEGF receptor 3 signaling.3Dietrich T. Bock F. Yuen D. Hos D. Bachmann B.O. Zahn G. Wiegand S. Chen L. Cursiefen C. Cutting edge: lymphatic Vessels. Not blood vessels, primarily mediate immune rejections after transplantation.J Immunol. 2010; 184: 535-539Crossref PubMed Scopus (230) Google Scholar The presence of lymphatic vessels in the cornea before transplantation significantly reduced graft success via the trafficking of graft antigens to the regional LNs.3Dietrich T. Bock F. Yuen D. Hos D. Bachmann B.O. Zahn G. Wiegand S. Chen L. Cursiefen C. Cutting edge: lymphatic Vessels. Not blood vessels, primarily mediate immune rejections after transplantation.J Immunol. 2010; 184: 535-539Crossref PubMed Scopus (230) Google Scholar Moreover, excision of the draining LNs before transplantation increased graft survival to 90%, even under high-risk settings.4Chen L. Hamrah P. Cursiefen C. Zhang Q. Pytowski B. Streilein J. Dana M. Vascular ednothelial growth factor receptor-3 mediates induction of corneal alloimmunity.Nat Med. 2004; 10: 813-815Crossref PubMed Scopus (190) Google Scholar Herpes simplex virus type-1 (HSV-1) is among the most successful of human pathogens with a seroprevalence rate between 50% to 80%.5Howard M. Sellors J.W. Jang D. Robinson N.J. Fearon M. Kaczorowski J. Chernesky M. Regional distribution of antibodies to herpes simplex virus type 1 (HSV-1) and HSV-2 in men and women in Ontario.Canada, J Clin Microbiol. 2003; 41: 84-89Crossref PubMed Scopus (51) Google Scholar Regardless of treatment, infection is lifelong due to the virus establishing a latent infection in sensory neurons, thereby evading immune detection.6Taylor T. Brockman M. McNamee E. Knipe D. Herpes simplex virus.Front Biosci. 2002; 7: 752-764Crossref PubMed Scopus (107) Google Scholar On reactivation, the virus replicates and travels by anterograde transport to the primary site of infection or other epithelial surfaces fed by the infected sensory nerve fibers.6Taylor T. Brockman M. McNamee E. Knipe D. Herpes simplex virus.Front Biosci. 2002; 7: 752-764Crossref PubMed Scopus (107) Google Scholar The most common clinical manifestation of HSV-1 infection is orolabial lesions; however, the virus can also be transported to the cornea resulting in recurring bouts of inflammatory keratitis.7Rowe A.M. St. Leger A.J. Jeon S. Dhaliwal D.K. Knickelbein J.E. Hendricks R.L. Herpes keratitis.Prog Retin Eye Res. 2012; 32: 88-101Crossref PubMed Scopus (205) Google Scholar The clinical signs of herpes stromal keratitis include stromal opacity, edema, and neovascularization.7Rowe A.M. St. Leger A.J. Jeon S. Dhaliwal D.K. Knickelbein J.E. Hendricks R.L. Herpes keratitis.Prog Retin Eye Res. 2012; 32: 88-101Crossref PubMed Scopus (205) Google Scholar The occurrence of corneal edema is believed to allow for easier growth of new vessels between collagen lamellae.8Bock F. Maruyama K. Regenfuss B. Hos D. Steven P. Heindl L.M. Cursiefen C. Novel anti(lymph)angiogenic treatment for corneal and ocular surface diseases.Prog Retin Eye Res. 2013; 34: 89-124Crossref PubMed Scopus (129) Google Scholar Recent studies have highlighted the importance of DNA sensor IFI-16/p204-driven type 1 interferon (IFN) signaling by infected corneal epithelial cells in controlling viral replication through the recruitment of inflammatory monocytes.9Conrady C.D. Zheng M. Fitzgerald K.A. Liu C. Carr D.J.J. Resistance to HSV-1 infection in the epithelium resides with the novel innate sensor, IFI-16.Mucosal Immunol. 2012; 5: 173-183Crossref PubMed Scopus (98) Google Scholar, 10Conrady C. Zheng M. Mandal N. van Rooijen N. Carr D. IFN-α-driven CCL2 production recruits inflammatory monocytes to infection site in mice.Mucosal Immunol. 2013; 6: 45-55Crossref PubMed Scopus (65) Google Scholar The development of lymphatic vessels into the central cornea after ocular HSV-1 infection has been described recently.11Wuest T.R. Carr D.J.J. VEGF-A expression by HSV-1-infected cells drives corneal lymphangiogenesis.J Exp Med. 2010; 207: 101-115Crossref PubMed Scopus (147) Google Scholar Ocular infection with HSV-1 was found to elicit resident epithelial cell expression of the pro-lymphangiogenic factor, VEGF-A, in the cornea that required binding of the HSV-1 encoded immediate to early transcription factor, ICP4, to Sp1 sites within the VEGF-A promoter.12Wuest T. Zheng M. Efstathiou S. Halford W.P. Carr D.J. The herpes simplex virus-1 transactivator infected cell protein-4 drives VEGF-A dependent neovascularization.PLoS Pathog. 2011; 7: e1002278Crossref PubMed Scopus (43) Google Scholar Subsequent release of VEGF-A by HSV-1–infected corneal epithelial cells during acute infection is thought to lead to robust lymphangiogenesis in the cornea proper, preceding the development of blood vessels.11Wuest T.R. Carr D.J.J. VEGF-A expression by HSV-1-infected cells drives corneal lymphangiogenesis.J Exp Med. 2010; 207: 101-115Crossref PubMed Scopus (147) Google Scholar It has also been noted that HSV-1 drives vascularization of the cornea by reducing the expression of soluble VEGFR1, which functions as a VEGF-A trap, blocking any downstream signaling.13Suryawanshi A. Mulik S. Sharma S. Reddy P.B.J. Sehrawat S. Rouse B.T. ocular neovascularization caused by herpes simplex virus type 1 infection results from breakdown of binding between vascular endothelial growth factor A and its soluble receptor.J Immunol. 2011; 186: 3653-3665Crossref PubMed Scopus (60) Google Scholar We show that impairment of type 1 IFN signaling results in extensive corneal edema and loss of epithelial due to robust replication of the virus within the tissue and recruitment Moreover, HSV-1 lymphatic vessels, but blood vessels during acute infection in the cornea and draining LN. wild-type mice from The mice from deficient in the type I IFN receptor B. C. A.J. to infection in Immunol. PubMed Scopus (51) Google Scholar on a at Eye treatment was consistent with the of on the and of by the of and Eye and and HSV-1 or M. Halford W.P. in herpes simplex 2010; 5: PubMed Scopus Google Scholar to and mice as C.D. Zheng M. Fitzgerald K.A. Liu C. Carr D.J.J. Resistance to HSV-1 infection in the epithelium resides with the novel innate sensor, IFI-16.Mucosal Immunol. 2012; 5: 173-183Crossref PubMed Scopus (98) Google Scholar HSV-1 viral in the tissue at by Blood endothelial cell and infected with HSV-1 at a of infection of 5 for with of HSV-1 a imaging with a was for imaging of HSV-1-infected and CD118−/− mice with a the corneal epithelial the of infected and CD118−/− mice with and under using the system G. B. A. B. G. K. M. M. of central corneal among of 2010; PubMed Scopus Google Scholar an that between the and central cornea was for central corneal of and infected and CD118−/− mice at the as by the these a of infected and CD118−/− mice on 3 and and at the of the with tissue and for of corneal and infected and CD118−/− at the The for at and to 5 on and with with a and the of epithelial and corneal in central into the cornea proper or in the lymph nodes of and infected mice was as C. Zheng M. Mandal N. van Rooijen N. Carr D. IFN-α-driven CCL2 production recruits inflammatory monocytes to infection site in mice.Mucosal Immunol. 2013; 6: 45-55Crossref PubMed Scopus (65) Google Scholar by and CD118−/− mice with of mice with 3 cells from or CD118−/− mice. The cells to the was by on in which found to be composed of to cells. from infected and mice and as T.R. Carr D.J.J. VEGF-A expression by HSV-1-infected cells drives corneal lymphangiogenesis.J Exp Med. 2010; 207: 101-115Crossref PubMed Scopus (147) Google Scholar and for antigens as Jang C. D. B. M. S. S. G. lymph lymphatic vessel 2011; 34: PubMed Scopus Google Scholar with a and using to expression was as described using T.R. Carr D.J.J. VEGF-A expression by HSV-1-infected cells drives corneal lymphangiogenesis.J Exp Med. 2010; 207: 101-115Crossref PubMed Scopus (147) Google Scholar and and in the as cornea the cells with primary HSV-1 infection of and cells for HSV-1 in the visual using a with a for or for in the visual and cells by The of cells was compared with the of cells in visual to of HSV-1 cells. using an with and CD118−/− mice to to the mice using a imaging system to of fluid by of the that using the mice and and for and or VEGF-A by a system as C.D. M. T. Carr D.J.J. of lymph integrity is associated with an in to HSV-1 infection in Immunol. PubMed Scopus Google Scholar was by to the The of tissue was to the of of tissue and was and into as T.R. Carr D.J.J. VEGF-A expression by HSV-1-infected cells drives corneal lymphangiogenesis.J Exp Med. 2010; 207: 101-115Crossref PubMed Scopus (147) Google Scholar The of VEGF-A, and to the was as The was to with of or analysis of with for and using a I IFN production by HSV-1 sensor in corneal epithelial cells is critical for virus C. Zheng M. Mandal N. van Rooijen N. Carr D. IFN-α-driven CCL2 production recruits inflammatory monocytes to infection site in mice.Mucosal Immunol. 2013; 6: 45-55Crossref PubMed Scopus (65) Google Scholar the type I IFN pathway tissue pathology in the cornea is the corneal pathology during acute HSV-1 infection in the absence of IFN and CD118−/− mice infected with HSV-1 and to pathology on day 5 revealed that CD118−/− mice with of associated with stromal keratitis and and and In corneal and a cornea of the of the imaging on and 5 revealed a loss of the corneal epithelium as by of the corneal surface of CD118−/− mice compared with the infected cornea with this CD118−/− mice in central corneal as by on 3 and and a in corneal on day 3 compared with the infected analysis revealed a loss of epithelial of the infected cornea of CD118−/− mice on 3 and 5 with increased corneal on day 5 epithelial cell loss was with the of virus from CD118−/− results in and pathological and epithelial and CD118−/− mice infected with of HSV-1 or remained as at 3 and 5 and and for of of the of infected and CD118−/− infected on day 5 The of corneal epithelial and corneal in CD118−/− and mice, using from as show in A and B. between the viral and the of corneal epithelial by and in CD118−/− at the are as the of to of to with CD118−/− mice by HSV-1 infection of the cornea results in and van Rooijen N. J.E. of in herpes simplex virus type 1 growth after ocular 41: Google Scholar, T. Chen S. J. of virus replication after herpes simplex virus type 1 infection of the PubMed Google Scholar, D.J.J. T. J. in herpes simplex virus type 1 in the of the is to a in cell in mice deficient in Res. 2008; PubMed Scopus Google Scholar the of the innate immune response in the HSV-1-infected CD118−/− with analysis was On 3 and 5 CD118−/− cells as as inflammatory monocytes compared with infected cornea day 5 the was in the CD118−/− whereas there was a in the of in the of as was in the of in the cornea of infected CD118−/− mice, be by in we examined and of which have been found to be in the cornea of HSV-1-infected mice the trafficking of monocytes and The role of in innate and adaptive Immunol. 2002; PubMed Scopus Google Scholar, D.J.J. L. Herpes simplex virus and the that mediate the Immunol. PubMed Scopus Google Scholar S. Leger A.J. Knickelbein J. A. M. 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The herpes simplex virus-1 transactivator infected cell protein-4 drives VEGF-A dependent neovascularization.PLoS Pathog. 2011; 7: e1002278Crossref PubMed Scopus (43) Google Scholar and CD118−/− mice a viral in the cornea, CD118−/− mice extensive lymphatic vessel development in with mice. this was found to be on day 3 CD118−/− mice significantly lymphatic vessel A and However, by day 5 the lymphatic vessels in CD118−/− mice A and The loss was selective for lymphatic blood vessels remained infection of CD118−/− mice with HSV-1 revealed of the virus in the peripheral cornea on day lymphatic vessels a for compared with human and in and infected with The of and cells was to infection in This is in to was in blood vessel integrity was after structural differences in that blood vessels and lymphatic vessels The viral results in the loss of lymphatic vessels in the this mice infected with an of in mice infected with a in lymphatic vessel integrity compared with mice infected with for a in lymphangiogenesis include reduced expression of pro-lymphangiogenic factors such as VEGF-A, and However, analysis revealed an in VEGF-A and expression in CD118−/− mice VEGF-A also significantly after HSV-1 infection of CD118−/− mice for Therefore, that the factor that drives lymphangiogenesis after HSV-1 VEGF-A, was in the CD118−/− mice compared with animals. for a loss of lymphatic vessel is the expression of the that to the factor that drives HSV-1-induced lymphangiogenesis during acute T.R. Carr D.J.J. VEGF-A expression by HSV-1-infected cells drives corneal lymphangiogenesis.J Exp Med. 2010; 207: 101-115Crossref PubMed Scopus (147) Google Scholar of expression revealed in expression to CD118−/− mice infected CD118−/− mice are deficient in VEGF-A or receptor of VEGF-A, and by and to the on day 5 3 to VEGF-A in the cornea by before and after HSV-1 infection of and CD118−/− mice 5 the targeting of lymphatic vessels by the of resident and epithelial and cells was using CD118−/− and from of CD118−/− and CD118−/− of significantly virus of resident cells and are in viral in the cornea vessel was in mice in which the resident cell a type I IFN pathway and these results that in addition to virus and of the VEGF-A, and factors to type I IFN signaling within resident cells facilitate the maintenance of lymphatic vessels within the cornea after HSV-1 The of CD118−/− mice to ocular HSV-1 infection results in the of the virus to the draining within C.D. M. T. Carr D.J.J. of lymph integrity is associated with an in to HSV-1 infection in Immunol. PubMed Scopus Google Scholar the virus is in the after day 5 in CD118−/− C.D. Zheng M. van Rooijen N. D. A. Carr D.J. and a functional type I IFN pathway are required to and Immunol. 2013; PubMed Scopus Google Scholar is that the virus to the or via resident cells that via the lymphatics to the after CCL21 The of infection is by a of the tissue compared with The in is due to the of cell the initial of cells is by day 5 C.D. M. T. Carr D.J.J. of lymph integrity is associated with an in to HSV-1 infection in Immunol. PubMed Scopus Google Scholar resonance imaging analysis revealed extensive edema in the of CD118−/− mice compared with mice and to is found in the cornea, we that the of lymphatic vessels by HSV-1 replication and lead to fluid Therefore, lymphatic vessels from infected and CD118−/− mice via confocal microscopy of vessels revealed a in the by lymphatic vessels in the CD118−/− mice compared with mice the loss of lymphatic vessel in the of CD118−/− mice with the pathology due to an to drain the fluid via the lymphatics as a of in the lymphatic structural a structural of the lymphatics by a loss of cells, or a of the visual is in to the of the cornea and the at the of ocular development that such as of the most successful of tissue J. and of corneal Rev Immunol. 2002; PubMed Scopus Google Scholar However, a in the that maintain this or can have results on visual acuity. this the the of that in the development of corneal pathology during acute HSV-1 infection that are in the absence of a functional type I IFN pathway. The pathology with CD118−/− mice are the HSV-1-infected mice with a cornea, the of the infected CD118−/− mice with loss of epithelial cells. The epithelial was the of virus replication due to the of CD118−/− mice to viral In epithelial cell loss and also be a of the in by day 5 with the in In addition to other in the cornea found to be between and CD118−/− mice. Specifically, cells, inflammatory and in the cornea of mice. results are consistent with the central role of inflammatory monocytes in HSV-1 in the cornea early during acute C. Zheng M. Mandal N. van Rooijen N. Carr D. IFN-α-driven CCL2 production recruits inflammatory monocytes to infection site in mice.Mucosal Immunol. 2013; 6: 45-55Crossref PubMed Scopus (65) Google Scholar The recruitment of these cells expression of vascular such as 1 which found to be necessary to ocular S. P. Carr D.J.J. is required for to herpes simplex virus type 1 but PubMed Scopus Google Scholar and K. T. E. K. M. expression of and the of inflammatory cells in the cornea and its associated PubMed Scopus Google Scholar we that the expression of but was whereas was in the of CD118−/− mice after HSV-1 to is in the C.D. M. T. Carr D.J.J. of lymph integrity is associated with an in to HSV-1 infection in Immunol. PubMed Scopus Google Scholar the of immune cells into the cornea is to this expression or due to other factors is to we that the expression into the cornea after HSV-1 as using Carr D.J.J. mice are to but herpes simplex virus type 1 corneal 2012; PubMed Scopus Google Scholar In the we of lymphatic vessel loss due to HSV-1 In the of of the virus can lymphangiogenesis in the however, as the virus lymphatic vessel integrity is The presence of lymphatic vessels in the cornea of CD118−/− mice is due to reduced expression of pro-lymphangiogenic factors or CD118−/− and revealed that the increased viral for lymphatic vessel factors that on type I IFN signaling be required to maintain lymphatic Ocular infection of CD118−/− mice with HSV-1 results in the of the virus to the as early as day C.D. M. T. Carr D.J.J. of lymph integrity is associated with an in to HSV-1 infection in Immunol. PubMed Scopus Google Scholar from the that the loss in lymphatics results in The lymphatic vessels or lymphatic that are or are ocular HSV-1 CD118−/− corneal lymphatics are by day 5 However, we that the lymphatic vessels from other to drain into the lymphatic vessels are in the draining of integrity is even in the presence of lymphatic vessel can occur via infection of with However, we that other factors also contribute to the of lymphatic vessels in studies have that VEGF-A in can lymphangiogenesis in the downstream C. B. M. VEGF-A by tissue induces lymphangiogenesis in draining lymph PubMed Scopus Google Scholar the increased VEGF-A found in CD118−/− with an in We that HSV-1 the expression of pro-lymphangiogenic factors by cell within the studies have cells and cells as of VEGF-A within the of and lymph during Immunol. 2012; PubMed Scopus Google Scholar, F. J. L. M. M. lymphangiogenesis in lymph nodes cell PubMed Scopus Google Scholar factors that lymphangiogenesis include growth factor and J.D. Lymphatics: at the interface of immunity, tolerance, and tumor metastasis.Microcirculation. 2011; 18: 517-531Crossref PubMed Scopus (14) Google Scholar the of by HSV-1 in reduced CCL21 and the recruitment of CCR7+ cells to the thereby the generation of an adaptive immune initial in the cornea and that HSV-1 viral can lymphatic vessels resulting in tissue We the structural differences that between blood and lymphatic capillaries for the selective loss in lymphatic vessels within the cornea and Blood vessel endothelial cells form tight junctions and are surrounded by a basement membrane and layer of smooth muscle cells, whereas lymphatic capillaries a basement membrane and between endothelial T. Alitalo K. Molecular biology and pathology of lymphangiogenesis.Annu Rev Pathol. 2008; 3: 367-397Crossref PubMed Scopus (285) Google Scholar has that the basement membrane the of Herpes simplex virus 1 and is by the basement PubMed Scopus Google Scholar With these we a for HSV-1 at viral in which HSV-1 lymphangiogenesis through and fluid of the infected tissue is However, as the virus replicates to HSV-1 but blood through infection of resulting in a loss of vessel integrity and fluid This also function in the of or of the most common clinical of HSV-1 in the human We P. Halford for the HSV-1 and for the CD118−/− mice. and and and in the of the with to the site of lymphatic vessel in the expression in the cornea of mice and CD118−/− mice. The mice infected with of HSV-1 the the mice and the and for lymphatic vessel vessels or cells. cells or a loss of expression in mice on day 3 and loss of of lymphatic vessels in CD118−/− by day 5 This in of that are in the of The of

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