Role of CXCR3 in the Immune Response to Murine Gam
http://www.100md.com
病菌学杂志 2005年第14期
La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr., San Diego, California 92121;
Department of Pediatrics, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115; and
College of Veterinary Medicine, Chonnam National University, Gwanju, South Korea
ABSTRACT
The chemokine IP-10 (CXCL10) and its cellular receptor CXCR3 are upregulated in the lung during murine gammaherpesvirus 68 (MHV-68) infection. In order to determine the role of the CXCR3 chemokine receptor in the immune response to MHV-68, CXCR3–/– mice were infected with the virus. CXCR3–/– mice showed delayed clearance of replicating MHV-68 from the lungs. This correlated with delayed T-cell recruitment to the lungs and reduced cytolytic activity prior to viral clearance. Splenomegaly and the numbers of latently infected cells per spleen were transiently increased. However, CXCR3–/– mice showed normal virus-specific antibody titers and effective long-term control of MHV-68 infection.
TEXT
Intranasal administration of murine gammaherpesvirus 68 (MHV-68) results in acute productive infection of lung alveolar epithelial cells and a latent infection in several cell types (7, 17, 19, 24). Infectious virus is cleared from the lungs by a T-cell-mediated process (6, 20), whereas control of latent virus, once established, can be mediated by either T- or B-cell-dependent mechanisms (1, 9, 17). We previously showed that that both CXCR3 and its ligand IP-10 (CXCL10 or crg-2) were upregulated in the lungs of MHV-68-infected mice (15). Furthermore, our in vitro studies showed that neutralizing antibodies to IP-10 significantly reduced the chemotactic activity of bronchoalveolar lavage (BAL) fluid (15). Other groups have also reported that the CXCR3 ligands MIG (CXCL9) and IP-10 are upregulated in the lungs and spleens of MHV-68-infected mice (5, 25). CXCR3 and its ligands have been reported to play a role in the clearance and/or inflammatory responses to mouse hepatitis virus (10), lymphocytic choriomeningitis virus (3), herpes simplex type 1 (2), and vaccinia and ectromelia viruses (8, 11-13), whereas the neutralization of IP-10 in Theiler's virus infection had no effect on inflammation or viral persistence (21). Our previous studies (23) showed that the absence of CXCR3 had a modest effect on pulmonary inflammation during influenza virus infection and did not affect viral clearance. Thus, the role and influence of CXCR3 and its ligands varies during infection with different viruses. In the present study, we examined the importance of CXCR3 in the immune response to MHV-68.
Age- and sex-matched 6- to 12-week-old CXCR3–/– mice, which had been backcrossed for 10 generations to C57BL/6 (Jackson) mice, and wild-type CXCR3+/+ C57BL/6 (Jackson) controls were used in all experiments. Mice were bred and housed under specific-pathogen-free conditions in the Animal Resource Center at the La Jolla Institute for Allergy and Immunology or Torrey Pines Institute for Molecular Studies. The genotypes of the CXCR3+/+ and CXCR3–/– mice were verified by PCR on tail snips.
Our previous studies (15) suggested that upregulation of CXCR3 on activated T cells might be a key event in T-cell trafficking to the lung during MHV-68 infection and consequent viral clearance. In accordance with this hypothesis, mice homozygous for a targeted disruption of the CXCR3 gene showed a significant delay in viral clearance from the lungs (Fig. 1A). Thus, lung viral titers of CXCR3–/– mice were significantly higher than those of CXCR3+/+ mice at days 7 to 10 postinfection (p.i.). By day 10 postinfection, all of the CXCR3+/+ mice had cleared virus, whereas only one of six CXCR3–/– mice had done so. However, by day 13 postinfection, all of the CXCR3–/– mice had also cleared replicating virus from their lungs. Furthermore, CXCR3–/– mice were able to maintain effective long-term control of MHV-68, and no viral reactivation was observed in the lungs.
The total number of cells infiltrating the lungs of CXCR3+/+ mice was significantly higher than the number of cells infiltrating the lungs of CXCR3–/– mice at days 7 (P < 0.001) and 8 (P < 0.01) postinfection (Fig. 1B). There was no significant difference in the total cell counts in BALs at day 10 and at any subsequent time point after infection. The proportion of CD8+ T cells in the BAL of CXCR3–/– mice were reduced compared to the proportion in the BAL of wild-type mice at days 7 to 10 postinfection (P < 0.05) (Fig. 2). There was also a significant reduction in the proportion of /? T-cell receptor-positive (?TCR+) cells in the BAL of CXCR3–/– mice at days 8 and 10 postinfection (P was <0.05 at each time point) but not at day 7 (possibly due to a slight increase in the proportion of CD4 T cells offsetting the reduction in CD8 T cells at the latter time point). The proportions of CD8 cells in the BALs of CXCR3–/– and wild-type mice by day 15 after infection were similar. Thus, there appeared to be a delay in CD8 T-cell trafficking to the lungs in CXCR3–/– mice. There was no significant difference in the proportions of DX5+ lymphocytes (predominantly NK cells) or CD19+ B cells in the BALs of CXCR3+/+ and CXCR3–/– mice at any time point, suggesting that CXCR3 is not required for trafficking of these cell types to the lung.
There was a significant reduction in the cytotoxic T lymphocyte (CTL) response in the BAL of CXCR3–/– mice at day 8 after infection (P < 0.01) (Fig. 3A), consistent with the subsequent delay in viral clearance in these mice (Fig. 1). Cytotoxicity was measured by using a redirected chromium release assay (1), which measures both virus-specific and nonspecific cytotoxicity. A previous publication (1) and our unpublished data (F. Giannoni and S. Sarawar, unpublished data) suggest that the majority of the redirected cytotoxic activity is mediated by CD3+CD8+ cells in this model of MHV-68 infection. The reduction in CTL activity did not seem to be explicable on a per-cell basis by the relative numbers of CD8 T cells in the BAL of CXCR3+/+ or CXCR3–/– mice. This suggests that there might have been a selective effect either on the trafficking of a subset of CD8 T cells in CXCR3–/– mice or, as has been shown in other models (4), that CXCR3 may play a role in T-cell activation. However, by day 10 after infection, there was less difference between cytotoxic T cell responses in BALs from wild-type and CXCR3–/– mice, (Fig. 3A), which is also consistent with the ensuing viral clearance in the CXCR3–/– mice. The CTL response in both CXCR3+/+ and CXCR3–/– mice was too low to measure at day 7 postinfection.
Serum antibody titers were determined by enzyme-linked immunosorbent assay 50 days after infection with MHV-68 as described previously (16). There was no significant difference in the total virus-specific serum antibody titers or antibody subclass distributions in CXCR3+/+ and CXCR3–/– mice. (Fig. 3B).
Following intranasal infection with MHV-68, latency is established in the spleen and splenomegaly is induced (18, 22). Splenomegaly in CXCR3–/– mice was significantly increased (Fig. 4A and B) whether measured by increased spleen weight (P was <0.01 at days 13 and 15 p.i., and P was <0.001 at day 17 p.i.) or cellularity (P was <0.01 at day 17 p.i.). The frequencies of latently infected cells enumerated in the spleens of wild-type and CXCR3–/– mice by using an infectious centers assay were similar (Fig. 4C). However, the total number of latently infected cells in CXCR3–/– mice was significantly increased (P was <0.05 at day 17 p.i.) (Fig. 4D) due to the overall increase in splenic cellularity. Little or no replicating virus (<3 PFU/107 splenocytes) was detected in the spleens of either CXCR3–/– or CXCR3+/+ mice. The percentage of CD8 T cells in the spleens of CXCR3–/– mice was higher than that for wild-type mice at days 10 to 13 after infection (Fig. 2), although CTL activity was not significantly affected (Fig. 3A). The increase in CD8 T-cell numbers may have been too small to increase CTL activity significantly. Alternatively, the increase may have predominantly involved CD8 T cells lacking cytolytic activity. These data suggest that the increase in splenomegaly and latently infected cells was not due to a decrease in CD8 T cells or CTL activity in the spleens of CXCR3–/– mice. Furthermore, there was no significant change in the number of splenic NK cells in CXCR3–/– mice. It is possible that the increased splenomegaly in CXCR3–/– mice reflects the delayed viral clearance in the lung, which leads to increased or prolonged seeding of latency in the spleen. Splenomegaly was eventually resolved in CXCR3–/– mice and effective long-term control of latent MHV-68 was established.
Taken together, our data suggest that the delay in viral clearance in CXCR3–/– mice results from an early reduction in T-cell trafficking to the lung and delayed development of the CTL response. However, the mice do eventually mount an effective immune response to MHV-68, and it is likely that both CTL and antiviral antibody responses contribute to the long-term control of MHV-68 in CXCR3–/– mice. A wide variety of chemokine receptors are upregulated on T cells during activation, and it is not unexpected that there would be some degree of functional overlap between them. The fact that T cells eventually migrated to the lungs and cleared replicating MHV-68 in the absence of CXCR3 suggests that they were responding via alternative chemokine receptors. We have previously shown that, in addition to CXCR3, chemokine receptors CCR1, CCR2, CCR3, and CCR5 are upregulated in the lungs during MHV-68 infection (15). The increased expression of these receptors coincides with the development of the inflammatory infiltrate, suggesting that they may also be involved in T-cell trafficking to the lungs (15). Therefore, it is likely that in the absence of CXCR3, T cells are able to respond via one or more of these receptors to chemokines produced in the lung. However, the initial impairment in viral control in mice lacking CXCR3 or its ligand observed in this study and previous studies of other systems (2-4, 8, 10-12) suggests that this chemokine-receptor interaction plays a unique role in the immune response.
ACKNOWLEDGMENTS
This work was supported in part by grant AI-44247 (S.R.S.) from the National Institutes of Health and by a grant from the Infectious Disease Science Center.
REFERENCES
Cardin, R. D., J. W. Brooks, S. R. Sarawar, and P. C. Doherty. 1996. Progressive loss of CD8+ T cell-mediated control of a gamma-herpesvirus in the absence of CD4+ T cells. J. Exp. Med. 184:863-871.
Carr, D. J., J. Chodosh, J. Ash, and T. E. Lane. 2003. Effect of anti-CXCL10 monoclonal antibody on herpes simplex virus type 1 keratitis and retinal infection. J. Virol. 77:10037-10046.
Christensen, J. E., A. Nansen, T. Moos, B. Lu, C. Gerard, J. P. Christensen, and A. R. Thomsen. 2004. Efficient T-cell surveillance of the CNS requires expression of the CXC chemokine receptor 3. J. Neurosci. 24:4849-4858.
Dufour, J. H., M. Dziejman, M. T. Liu, J. H. Leung, T. E. Lane, and A. D. Luster. 2002. IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking. J. Immunol. 168:3195-3204.
Ebrahimi, B., B. M. Dutia, D. G. Brownstein, and A. A. Nash. 2001. Murine gammaherpesvirus-68 infection causes multi-organ fibrosis and alters leukocyte trafficking in interferon-gamma receptor knockout mice. Am. J. Pathol. 158:2117-2125.
Ehtisham, S., N. P. Sunil-Chandra, and A. A. Nash. 1993. Pathogenesis of murine gammaherpesvirus infection in mice deficient in CD4 and CD8 T cells. J. Virol. 67:5247-5252.
Flano, E., S. M. Husain, J. T. Sample, D. L. Woodland, and M. A. Blackman. 2000. Latent murine gamma-herpesvirus infection is established in activated B cells, dendritic cells, and macrophages. J. Immunol. 165:1074-1081.
Hamilton, N. H., S. Mahalingam, J. L. Banyer, I. A. Ramshaw, and S. A. Thomson. 2004. A recombinant vaccinia virus encoding the interferon-inducible T-cell alpha chemoattractant is attenuated in vivo. Scand. J. Immunol. 59:246-254.
Kim, I. J., E. Flano, D. L. Woodland, and M. A. Blackman. 2002. Antibody-mediated control of persistent gamma-herpesvirus infection. J. Immunol. 168:3958-3964.
Liu, M. T., B. P. Chen, P. Oertel, M. J. Buchmeier, D. Armstrong, T. A. Hamilton, and T. E. Lane. 2000. The T cell chemoattractant IFN-inducible protein 10 is essential in host defense against viral-induced neurologic disease. J. Immunol. 165:2327-2330.
Mahalingam, S., J. M. Farber, and G. Karupiah. 1999. The interferon-inducible chemokines MuMig and Crg-2 exhibit antiviral activity in vivo. J. Virol. 73:1479-1491.
Mahalingam, S., P. S. Foster, M. Lobigs, J. M. Farber, and G. Karupiah. 2000. Interferon-inducible chemokines and immunity to poxvirus infections. Immunol. Rev. 177:127-133.
Mahalingam, S., and G. Karupiah. 2000. Expression of the interferon-inducible chemokines MuMig and Crg-2 following vaccinia virus infection in vivo. Immunol. Cell Biol. 78:156-160.
Sarawar, S. R., and P. C. Doherty. 1994. Concurrent production of interleukin-2, interleukin-10, and gamma interferon in the regional lymph nodes of mice with influenza pneumonia. J. Virol. 68:3112-3119.
Sarawar, S. R., B. J. Lee, M. Anderson, Y. C. Teng, R. Zuberi, and S. Von Gesjen. 2002. Chemokine induction and leukocyte trafficking to the lungs during murine gammaherpesvirus 68 (MHV-68) infection. Virology 293:54-62.
Sarawar, S. R., B. J. Lee, S. K. Reiter, and S. P. Schoenberger. 2001. Stimulation via CD40 can substitute for CD4 T cell function in preventing reactivation of a latent herpesvirus. Proc. Natl. Acad. Sci. USA 98:6325-6329.
Stewart, J. P., E. J. Usherwood, A. Ross, H. Dyson, and T. Nash. 1998. Lung epithelial cells are a major site of murine gammaherpesvirus persistence. J. Exp. Med. 187:1941-1951.
Sunil-Chandra, N. P., S. Efstathiou, J. Arno, and A. A. Nash. 1992. Virological and pathological features of mice infected with murine gamma-herpesvirus 68. J. Gen. Virol. 73:2347-2356.
Sunil-Chandra, N. P., S. Efstathiou, and A. A. Nash. 1992. Murine gammaherpesvirus 68 establishes a latent infection in mouse B lymphocytes in vivo. J. Gen. Virol. 73:3275-3279.
Topham, D. J., R. C. Cardin, J. P. Christensen, J. W. Brooks, G. T. Belz, and P. C. Doherty. 2001. Perforin and Fas in murine gammaherpesvirus-specific CD8(+) T cell control and morbidity. J. Gen. Virol. 82:1971-1981.
Tsunoda, I., T. E. Lane, J. Blackett, and R. S. Fujinami. 2004. Distinct roles for IP-10/CXCL10 in three animal models, Theiler's virus infection, EAE, and MHV infection, for multiple sclerosis: implication of differing roles for IP-10. Mult. Scler. 10:26-34.
Usherwood, E. J., A. J. Ross, D. J. Allen, and A. A. Nash. 1996. Murine gammaherpesvirus-induced splenomegaly: a critical role for CD4 T cells. J. Gen. Virol. 77:627-630.
Wareing, M. D., A. B. Lyon, B. Lu, C. Gerard, and S. R. Sarawar. 2004. Chemokine expression during the development and resolution of a pulmonary leukocyte response to influenza A virus infection in mice. J. Leukoc. Biol. 76:886-895.
Weck, K. E., S. S. Kim, H. I. Virgin, and S. H. Speck. 1999. Macrophages are the major reservoir of latent murine gammaherpesvirus 68 in peritoneal cells. J. Virol. 73:3273-3283.
Weinberg, J. B., M. L. Lutzke, S. Efstathiou, S. L. Kunkel, and R. Rochford. 2002. Elevated chemokine responses are maintained in lungs after clearance of viral infection. J. Virol. 76:10518-10523.(Bong Joo Lee, Francesca G)
Department of Pediatrics, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115; and
College of Veterinary Medicine, Chonnam National University, Gwanju, South Korea
ABSTRACT
The chemokine IP-10 (CXCL10) and its cellular receptor CXCR3 are upregulated in the lung during murine gammaherpesvirus 68 (MHV-68) infection. In order to determine the role of the CXCR3 chemokine receptor in the immune response to MHV-68, CXCR3–/– mice were infected with the virus. CXCR3–/– mice showed delayed clearance of replicating MHV-68 from the lungs. This correlated with delayed T-cell recruitment to the lungs and reduced cytolytic activity prior to viral clearance. Splenomegaly and the numbers of latently infected cells per spleen were transiently increased. However, CXCR3–/– mice showed normal virus-specific antibody titers and effective long-term control of MHV-68 infection.
TEXT
Intranasal administration of murine gammaherpesvirus 68 (MHV-68) results in acute productive infection of lung alveolar epithelial cells and a latent infection in several cell types (7, 17, 19, 24). Infectious virus is cleared from the lungs by a T-cell-mediated process (6, 20), whereas control of latent virus, once established, can be mediated by either T- or B-cell-dependent mechanisms (1, 9, 17). We previously showed that that both CXCR3 and its ligand IP-10 (CXCL10 or crg-2) were upregulated in the lungs of MHV-68-infected mice (15). Furthermore, our in vitro studies showed that neutralizing antibodies to IP-10 significantly reduced the chemotactic activity of bronchoalveolar lavage (BAL) fluid (15). Other groups have also reported that the CXCR3 ligands MIG (CXCL9) and IP-10 are upregulated in the lungs and spleens of MHV-68-infected mice (5, 25). CXCR3 and its ligands have been reported to play a role in the clearance and/or inflammatory responses to mouse hepatitis virus (10), lymphocytic choriomeningitis virus (3), herpes simplex type 1 (2), and vaccinia and ectromelia viruses (8, 11-13), whereas the neutralization of IP-10 in Theiler's virus infection had no effect on inflammation or viral persistence (21). Our previous studies (23) showed that the absence of CXCR3 had a modest effect on pulmonary inflammation during influenza virus infection and did not affect viral clearance. Thus, the role and influence of CXCR3 and its ligands varies during infection with different viruses. In the present study, we examined the importance of CXCR3 in the immune response to MHV-68.
Age- and sex-matched 6- to 12-week-old CXCR3–/– mice, which had been backcrossed for 10 generations to C57BL/6 (Jackson) mice, and wild-type CXCR3+/+ C57BL/6 (Jackson) controls were used in all experiments. Mice were bred and housed under specific-pathogen-free conditions in the Animal Resource Center at the La Jolla Institute for Allergy and Immunology or Torrey Pines Institute for Molecular Studies. The genotypes of the CXCR3+/+ and CXCR3–/– mice were verified by PCR on tail snips.
Our previous studies (15) suggested that upregulation of CXCR3 on activated T cells might be a key event in T-cell trafficking to the lung during MHV-68 infection and consequent viral clearance. In accordance with this hypothesis, mice homozygous for a targeted disruption of the CXCR3 gene showed a significant delay in viral clearance from the lungs (Fig. 1A). Thus, lung viral titers of CXCR3–/– mice were significantly higher than those of CXCR3+/+ mice at days 7 to 10 postinfection (p.i.). By day 10 postinfection, all of the CXCR3+/+ mice had cleared virus, whereas only one of six CXCR3–/– mice had done so. However, by day 13 postinfection, all of the CXCR3–/– mice had also cleared replicating virus from their lungs. Furthermore, CXCR3–/– mice were able to maintain effective long-term control of MHV-68, and no viral reactivation was observed in the lungs.
The total number of cells infiltrating the lungs of CXCR3+/+ mice was significantly higher than the number of cells infiltrating the lungs of CXCR3–/– mice at days 7 (P < 0.001) and 8 (P < 0.01) postinfection (Fig. 1B). There was no significant difference in the total cell counts in BALs at day 10 and at any subsequent time point after infection. The proportion of CD8+ T cells in the BAL of CXCR3–/– mice were reduced compared to the proportion in the BAL of wild-type mice at days 7 to 10 postinfection (P < 0.05) (Fig. 2). There was also a significant reduction in the proportion of /? T-cell receptor-positive (?TCR+) cells in the BAL of CXCR3–/– mice at days 8 and 10 postinfection (P was <0.05 at each time point) but not at day 7 (possibly due to a slight increase in the proportion of CD4 T cells offsetting the reduction in CD8 T cells at the latter time point). The proportions of CD8 cells in the BALs of CXCR3–/– and wild-type mice by day 15 after infection were similar. Thus, there appeared to be a delay in CD8 T-cell trafficking to the lungs in CXCR3–/– mice. There was no significant difference in the proportions of DX5+ lymphocytes (predominantly NK cells) or CD19+ B cells in the BALs of CXCR3+/+ and CXCR3–/– mice at any time point, suggesting that CXCR3 is not required for trafficking of these cell types to the lung.
There was a significant reduction in the cytotoxic T lymphocyte (CTL) response in the BAL of CXCR3–/– mice at day 8 after infection (P < 0.01) (Fig. 3A), consistent with the subsequent delay in viral clearance in these mice (Fig. 1). Cytotoxicity was measured by using a redirected chromium release assay (1), which measures both virus-specific and nonspecific cytotoxicity. A previous publication (1) and our unpublished data (F. Giannoni and S. Sarawar, unpublished data) suggest that the majority of the redirected cytotoxic activity is mediated by CD3+CD8+ cells in this model of MHV-68 infection. The reduction in CTL activity did not seem to be explicable on a per-cell basis by the relative numbers of CD8 T cells in the BAL of CXCR3+/+ or CXCR3–/– mice. This suggests that there might have been a selective effect either on the trafficking of a subset of CD8 T cells in CXCR3–/– mice or, as has been shown in other models (4), that CXCR3 may play a role in T-cell activation. However, by day 10 after infection, there was less difference between cytotoxic T cell responses in BALs from wild-type and CXCR3–/– mice, (Fig. 3A), which is also consistent with the ensuing viral clearance in the CXCR3–/– mice. The CTL response in both CXCR3+/+ and CXCR3–/– mice was too low to measure at day 7 postinfection.
Serum antibody titers were determined by enzyme-linked immunosorbent assay 50 days after infection with MHV-68 as described previously (16). There was no significant difference in the total virus-specific serum antibody titers or antibody subclass distributions in CXCR3+/+ and CXCR3–/– mice. (Fig. 3B).
Following intranasal infection with MHV-68, latency is established in the spleen and splenomegaly is induced (18, 22). Splenomegaly in CXCR3–/– mice was significantly increased (Fig. 4A and B) whether measured by increased spleen weight (P was <0.01 at days 13 and 15 p.i., and P was <0.001 at day 17 p.i.) or cellularity (P was <0.01 at day 17 p.i.). The frequencies of latently infected cells enumerated in the spleens of wild-type and CXCR3–/– mice by using an infectious centers assay were similar (Fig. 4C). However, the total number of latently infected cells in CXCR3–/– mice was significantly increased (P was <0.05 at day 17 p.i.) (Fig. 4D) due to the overall increase in splenic cellularity. Little or no replicating virus (<3 PFU/107 splenocytes) was detected in the spleens of either CXCR3–/– or CXCR3+/+ mice. The percentage of CD8 T cells in the spleens of CXCR3–/– mice was higher than that for wild-type mice at days 10 to 13 after infection (Fig. 2), although CTL activity was not significantly affected (Fig. 3A). The increase in CD8 T-cell numbers may have been too small to increase CTL activity significantly. Alternatively, the increase may have predominantly involved CD8 T cells lacking cytolytic activity. These data suggest that the increase in splenomegaly and latently infected cells was not due to a decrease in CD8 T cells or CTL activity in the spleens of CXCR3–/– mice. Furthermore, there was no significant change in the number of splenic NK cells in CXCR3–/– mice. It is possible that the increased splenomegaly in CXCR3–/– mice reflects the delayed viral clearance in the lung, which leads to increased or prolonged seeding of latency in the spleen. Splenomegaly was eventually resolved in CXCR3–/– mice and effective long-term control of latent MHV-68 was established.
Taken together, our data suggest that the delay in viral clearance in CXCR3–/– mice results from an early reduction in T-cell trafficking to the lung and delayed development of the CTL response. However, the mice do eventually mount an effective immune response to MHV-68, and it is likely that both CTL and antiviral antibody responses contribute to the long-term control of MHV-68 in CXCR3–/– mice. A wide variety of chemokine receptors are upregulated on T cells during activation, and it is not unexpected that there would be some degree of functional overlap between them. The fact that T cells eventually migrated to the lungs and cleared replicating MHV-68 in the absence of CXCR3 suggests that they were responding via alternative chemokine receptors. We have previously shown that, in addition to CXCR3, chemokine receptors CCR1, CCR2, CCR3, and CCR5 are upregulated in the lungs during MHV-68 infection (15). The increased expression of these receptors coincides with the development of the inflammatory infiltrate, suggesting that they may also be involved in T-cell trafficking to the lungs (15). Therefore, it is likely that in the absence of CXCR3, T cells are able to respond via one or more of these receptors to chemokines produced in the lung. However, the initial impairment in viral control in mice lacking CXCR3 or its ligand observed in this study and previous studies of other systems (2-4, 8, 10-12) suggests that this chemokine-receptor interaction plays a unique role in the immune response.
ACKNOWLEDGMENTS
This work was supported in part by grant AI-44247 (S.R.S.) from the National Institutes of Health and by a grant from the Infectious Disease Science Center.
REFERENCES
Cardin, R. D., J. W. Brooks, S. R. Sarawar, and P. C. Doherty. 1996. Progressive loss of CD8+ T cell-mediated control of a gamma-herpesvirus in the absence of CD4+ T cells. J. Exp. Med. 184:863-871.
Carr, D. J., J. Chodosh, J. Ash, and T. E. Lane. 2003. Effect of anti-CXCL10 monoclonal antibody on herpes simplex virus type 1 keratitis and retinal infection. J. Virol. 77:10037-10046.
Christensen, J. E., A. Nansen, T. Moos, B. Lu, C. Gerard, J. P. Christensen, and A. R. Thomsen. 2004. Efficient T-cell surveillance of the CNS requires expression of the CXC chemokine receptor 3. J. Neurosci. 24:4849-4858.
Dufour, J. H., M. Dziejman, M. T. Liu, J. H. Leung, T. E. Lane, and A. D. Luster. 2002. IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking. J. Immunol. 168:3195-3204.
Ebrahimi, B., B. M. Dutia, D. G. Brownstein, and A. A. Nash. 2001. Murine gammaherpesvirus-68 infection causes multi-organ fibrosis and alters leukocyte trafficking in interferon-gamma receptor knockout mice. Am. J. Pathol. 158:2117-2125.
Ehtisham, S., N. P. Sunil-Chandra, and A. A. Nash. 1993. Pathogenesis of murine gammaherpesvirus infection in mice deficient in CD4 and CD8 T cells. J. Virol. 67:5247-5252.
Flano, E., S. M. Husain, J. T. Sample, D. L. Woodland, and M. A. Blackman. 2000. Latent murine gamma-herpesvirus infection is established in activated B cells, dendritic cells, and macrophages. J. Immunol. 165:1074-1081.
Hamilton, N. H., S. Mahalingam, J. L. Banyer, I. A. Ramshaw, and S. A. Thomson. 2004. A recombinant vaccinia virus encoding the interferon-inducible T-cell alpha chemoattractant is attenuated in vivo. Scand. J. Immunol. 59:246-254.
Kim, I. J., E. Flano, D. L. Woodland, and M. A. Blackman. 2002. Antibody-mediated control of persistent gamma-herpesvirus infection. J. Immunol. 168:3958-3964.
Liu, M. T., B. P. Chen, P. Oertel, M. J. Buchmeier, D. Armstrong, T. A. Hamilton, and T. E. Lane. 2000. The T cell chemoattractant IFN-inducible protein 10 is essential in host defense against viral-induced neurologic disease. J. Immunol. 165:2327-2330.
Mahalingam, S., J. M. Farber, and G. Karupiah. 1999. The interferon-inducible chemokines MuMig and Crg-2 exhibit antiviral activity in vivo. J. Virol. 73:1479-1491.
Mahalingam, S., P. S. Foster, M. Lobigs, J. M. Farber, and G. Karupiah. 2000. Interferon-inducible chemokines and immunity to poxvirus infections. Immunol. Rev. 177:127-133.
Mahalingam, S., and G. Karupiah. 2000. Expression of the interferon-inducible chemokines MuMig and Crg-2 following vaccinia virus infection in vivo. Immunol. Cell Biol. 78:156-160.
Sarawar, S. R., and P. C. Doherty. 1994. Concurrent production of interleukin-2, interleukin-10, and gamma interferon in the regional lymph nodes of mice with influenza pneumonia. J. Virol. 68:3112-3119.
Sarawar, S. R., B. J. Lee, M. Anderson, Y. C. Teng, R. Zuberi, and S. Von Gesjen. 2002. Chemokine induction and leukocyte trafficking to the lungs during murine gammaherpesvirus 68 (MHV-68) infection. Virology 293:54-62.
Sarawar, S. R., B. J. Lee, S. K. Reiter, and S. P. Schoenberger. 2001. Stimulation via CD40 can substitute for CD4 T cell function in preventing reactivation of a latent herpesvirus. Proc. Natl. Acad. Sci. USA 98:6325-6329.
Stewart, J. P., E. J. Usherwood, A. Ross, H. Dyson, and T. Nash. 1998. Lung epithelial cells are a major site of murine gammaherpesvirus persistence. J. Exp. Med. 187:1941-1951.
Sunil-Chandra, N. P., S. Efstathiou, J. Arno, and A. A. Nash. 1992. Virological and pathological features of mice infected with murine gamma-herpesvirus 68. J. Gen. Virol. 73:2347-2356.
Sunil-Chandra, N. P., S. Efstathiou, and A. A. Nash. 1992. Murine gammaherpesvirus 68 establishes a latent infection in mouse B lymphocytes in vivo. J. Gen. Virol. 73:3275-3279.
Topham, D. J., R. C. Cardin, J. P. Christensen, J. W. Brooks, G. T. Belz, and P. C. Doherty. 2001. Perforin and Fas in murine gammaherpesvirus-specific CD8(+) T cell control and morbidity. J. Gen. Virol. 82:1971-1981.
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