Ly49H+ NK Cells Migrate to and Protect Splenic White Pulp Stroma from Murine Cytomegalovirus Infection

Bekiaris, Vasileios; Timoshenko, O.S.; Hou, Tie Zheng; Toellner, Kai‐Michael; Shakib, Saba; Gaspal, Fabrina; McConnell, Fiona M.; Parnell, Sonia M.; Withers, David R.; Buckley, Christopher D.; Sweet, C.; Yokoyama, Wayne M.; Anderson, Graham; Lane, Peter J. L.

doi:10.4049/jimmunol.180.10.6768

Cited by 45 publications

(67 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Collectively, these results indicate that relatively lower MTHFR levels are associated with an enhanced control of acute MCMV infection. Uncontrolled MCMV replication is usually accompanied by massive production of pro-inflammatory cytokines, such as IFNa, IFNg and interleukin-12, and loss of spleen cell populations, which together contribute to MCMV-mediated pathology 23,24 In fact, detrimental effects of high levels of IFNa during viral infection have been observed 25,26 Abundant levels of IFNa can compromise host immune responses by inhibiting the differentiation of dendritic cells or by leading to CD8 þ T cell attrition 25,26 In contrast, MCMV-resistant mice showing low viral load present limited production of pro-inflammatory cytokines and increased specific subpopulations of spleen cells in comparison with susceptible mice 24,27 Thus, we monitored serum levels of IFNs at 1.5 days p.i., the peak of cytokine production and spleen cell numbers at 3 days p.i., the peak of cell loss. Mthfr À/À and Mthfr þ /À mice had lower cytokine levels than their wild-type counterparts even though the differences did not reach significance (Figure 1b).…”

Section: Resultsmentioning

confidence: 99%

Methylenetetrahydrofolate reductase (MTHFR) deficiency enhances resistance against cytomegalovirus infection

Fodil-Cornu

Kozij

et al. 2009

Genes Immun

View full text Add to dashboard Cite

Folates provide one-carbon units for nucleotide synthesis and methylation reactions. A common polymorphism in the MTHFR gene (677C-T) results in reduced enzymatic activity, and is associated with an increased risk for neural tube defects and cardiovascular disease. The high prevalence of this polymorphism suggests that it may have experienced a selective advantage under environmental pressure, possibly an infectious agent. To test the hypothesis that methylenetetrahydrofolate reductase (MTHFR) genotype influences the outcome of infectious disease, we examined the response of Mthfr-deficient mice against mouse cytomegalovirus (MCMV) infection. Acute MCMV infection of Mthfr À/À mice resulted in early control of cytokine secretion, decreased viral titer and preservation of spleen immune cells, in contrast to Mthfr wild-type littermates. The phenotype was abolished in MTHFR transgenic mice carrying an extra copy of the gene. Infection of primary fibroblasts with MCMV showed a decrease in viral replication and in the number of productively infected cells in Mthfr þ /À fibroblasts compared with wild-type cells. These results indicate that Mthfr deficiency protects against MCMV infection in vivo and in vitro, suggesting that human genetic variants may provide an advantage in the host response against certain pathogens.

show abstract

Section: Resultsmentioning

confidence: 99%

Methylenetetrahydrofolate reductase (MTHFR) deficiency enhances resistance against cytomegalovirus infection

Fodil-Cornu

Kozij

et al. 2009

Genes Immun

View full text Add to dashboard Cite

show abstract

“…Previous studies reported a transient migration of NK1.1 + cells [16], Ly49G2 + cells [17] or more recently Ly49H + cells [31] in the white pulp area of the spleen upon MCMV infection. These different reports were, however, limited by the specificity of the antibodies used or by the very low percentage of cells expressing the molecules that they recognized.…”

Section: Discussionmentioning

confidence: 99%

Intrasplenic trafficking of natural killer cells is redirected by chemokines upon inflammation

et al. 2008

View full text Add to dashboard Cite

The spleen is a major homing site for NK cells. How they traffic to and within this site in homeostatic or inflammatory conditions is, however, mostly unknown. Here we show that NK cells enter the spleen through the marginal sinus and home to the red pulp via a pertussis toxin-insensitive mechanism. Upon inflammation induced by poly(I:C) injection or mouse cytomegalovirus infection, many NK cells left the red pulp while others transiently entered the white pulp, predominantly the T cell area. This migration was dependent on both CXCR3 and CCL5, suggesting a synergy between CXCR3 and CCR5, and followed the path lined by fibroblastic reticular cells. Thus, the entry of NK cells in the white pulp is limited by the expression of pro-inflammatory chemokines. This phenomenon ensures the segregation of NK cells outside of the white pulp and might contribute to the control of immunopathology.Key words: Chemokines Á Migration Á Natural killer cells Á Spleen Supporting Information available online Introduction Natural killer (NK) cells are large granular lymphocytes involved in defense mechanisms against several types of microbial infections and tumors [1][2][3]. In particular in the mouse, NK cells play a critical role in the defense against mouse cytomegalovirus (MCMV) by eliminating infected cells through their cytotoxic activity [4] and by regulating the immune response through their crosstalk with dendritic cells [5,6]. Consistent with their role in immune surveillance, NK cells are widely distributed in the body. They are present in lymphoid organs as well as in non-lymphoid peripheral tissues [7]. At steady state, the spleen is the largest reservoir of mouse NK cells [8].The spleen has a complex architecture owing to its dual roles in the filtration of exhausted red blood cells and as a secondary lymphoid organ. Blood is supplied through arterioles that are FrontlineClaude GrØgoire et al. Eur. J. Immunol. 2008. 38: 2076-2084 We and others have previously reported that most NK cells are located in the red pulp area of the spleen with NK cells occasionally present in the white pulp [8,[16][17][18][19]. Moreover, previous reports have suggested that NK cell trafficking was modified in the case of inflammation [16,17], possibly by inflammatory chemokines that are known to act on NK cells [20]. However, the pattern of NK cell trafficking within the spleen is not known. In particular, the route of entry, the migration tracts, and the guidance signals that allow NK cells to enter or leave the red pulp are all issues that need to be addressed.We recently described that the cell surface expression of the activating NK cell receptor NKp46 (CD336) defines NK cells across mammalian species and that staining for NKp46 enables the unambiguous in situ visualization of NK cells in tissue sections [19]. We took advantage of this tool to analyze NK cell trafficking under steady-state and inflammatory conditions. Results NK cells enter the spleen through the marginal zoneWe sought to determine how NK cells enter the spleen and reac...

show abstract

“…CD45.1 ϩ transferred cells were detected in situ after staining with anti-mouse CD45.1-FITC (eBioscience). Sample preparation for and analysis of quantitative real-time PCR was as previously described (14,19). Primer/probe sequences (ccl19, ccl21, cxcl13, ␤-actin) were published previously (14).…”

Section: Confocal Microscopy and Quantitative Real-time Pcrmentioning

confidence: 99%

“…Tissue preparation, staining, and image acquisition and analysis were performed as previously described (14,19). B cells were detected after staining with anti-mouse IgM conjugated to Rhodamine red (Jackson ImmunoResearch Laboratories) or anti-mouse B220 conjugated to Pacific blue (eBioscience).…”

Section: Confocal Microscopy and Quantitative Real-time Pcrmentioning

confidence: 99%

CD30 Is Required for CCL21 Expression and CD4 T Cell Recruitment in the Absence of Lymphotoxin Signals

Bekiaris

Gaspal

Kim

et al. 2009

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Lymphoid tissue inducer cells express a diverse array of tumor necrosis family ligands, including those that bind CD30 and the lymphotoxin β receptor. Both of these signaling pathways have been linked with B/T segregation in the spleen. In this study, we have dissected a lymphotoxin-independent CD30-dependent signal for the induction of expression of the T zone chemokine, CCL21. Reduced expression of CCL21 due to CD30 deficiency was functionally significant: mice deficient in both lymphotoxin and CD30 (dKO) signals had significantly smaller accumulations of lymphocytes in their splenic white pulp areas, with no evidence of focal aggregation of T cells. Furthermore, recruitment of wild-type CD4 T cells was poor in dKO mice compared with both wild-type or lymphotoxin-deficient mice. Phylogeny suggests that CD30 signals predated those through the lymphotoxin β receptor. We suggest that CD30 signals from lymphoid tissue inducer cells were a primitive mechanism to recruit and prime CD4 T cells. This would have been a stepping stone in the evolution of the highly organized lymphotoxin dependent B and T white pulp areas within which CD4-dependent memory Ab responses now develop.

show abstract

Ly49H+ NK Cells Migrate to and Protect Splenic White Pulp Stroma from Murine Cytomegalovirus Infection

Cited by 45 publications

References 31 publications

Methylenetetrahydrofolate reductase (MTHFR) deficiency enhances resistance against cytomegalovirus infection

Methylenetetrahydrofolate reductase (MTHFR) deficiency enhances resistance against cytomegalovirus infection

Intrasplenic trafficking of natural killer cells is redirected by chemokines upon inflammation

CD30 Is Required for CCL21 Expression and CD4 T Cell Recruitment in the Absence of Lymphotoxin Signals

Contact Info

Product

Resources

About