Imaging of NKT cell recirculation and tissue migration during antimicrobial immunity
- Laboratory of Autoimmune Diabetes, Department of Microbiology and Immunology, Robarts Research Institute, Western University, London, ON, Canada
This Opinion article outlines the relative paucity and emphasizes the need to enhance our knowledge of how subsets of natural killer T (NKT) cells mediate immune mechanisms of elimination of microbial pathogens at sites of inflammation or infection. To date, most studies of how NKT cell subsets migrate upon antigen stimulation have focused on NKT cell activation in the spleen, lymph nodes (LN) and liver (1). Thus, there currently exists an unmet need to determine the patterns of recirculation and tissue migration of NKT cell subsets and interacting antigen-presenting cells (APCs) that occur at relevant mucosal surfaces in several other organs, including the lung, intestine, and colon. This article proposes and highlights the benefit of intravital cellular imaging in vivo of type I and type II NKT cell subsets as an important methodology that may enable the visualization of NKT–APC cellular interactions at mucosal surfaces and enhance the application of this methodology to clinical therapy of antimicrobial immunity.
T Cell Recirculation and Migration into Tissues
During an immune response, T cells and B cells traffic to and recirculate between blood and peripheral lymphoid tissues prior to activation by antigen (1). Chemokines attract T cells to various sites of interaction with antigen-presenting dendritic cells (DCs) in the spleen and LN. After further encounter with antigen, T cells divide and differentiate into effector T cells (Teff) that migrate to different sites of infection to combat and destroy microbial pathogens (2). Cytokines secreted by Teff also help to clear infectious pathogens from these sites. Interactions between T cells and DCs at various sites of inflammation in LN are crucial for promoting subsequent immunity to microbes (2). These observations underscore the importance of understanding how T cell recirculation, localization, and interaction in vivo in target tissues mediate effective immune responses that either trigger or prevent inflammation and antimicrobial immunity.
Type I and Type II NKT Cell Subsets
Little is known about the various factors that mediate the recirculation, localization, and interactions of subsets of NKT cells in vivo in target tissues and lead to antimicrobial immunity. NKT cells display surface T-cell antigen receptors (TCR) expressed by both conventional T cells and NK cells, such as CD56/161 (humans) and NK1.1 (mice) (3–5). NKT cells recognize lipid antigens presented by CD1d MHC class I like molecules (2–15) on various APCs, including DCs, macrophages (Mϕ), B cells, thymocytes, adipocytes, and hepatocytes. While the CD1a, CD1b, CD1c, CD1e, and MR1 MHC class I like molecules are also expressed on APCs and can activate various T cell subsets, only analyses of CD1d-mediated responses of type I and type II NKT cell subsets will be presented here. The development of type I NKT cells occurs in the thymus and depends on the activity of several transcription factors including promyelocytic leukemia zinc finger (PLZF), T box transcription factor (T-bet), retinoic acid receptor-related orphan receptor-γt (ROR-γt), and GATA-binding protein 3 (GATA-3) (2, 5).
Type I NKT cells respond to α- and β-linked glycolipids. For example, stimulation of type I NKT cells by the α-galactosylceramide (αGalCer) glycolipid agonist induces the secretion of many cytokines that elicit both Th1 [interferon-γ (IFN-γ)] and Th2 [interleukin-4 (IL-4) and IL-13] responses (2, 7–17). Type I NKT cells are more prevalent than type II NKT cells in mice than in humans (18–20), and comprise about 50% of murine intra-hepatic lymphocytes (21–23). The type I NKT cell invariant TCR is encoded mainly by a germline Vα gene (Vα14/Jα18 in mice and Vα24/JαQ in humans), and more diverse non-germline Vβ chain genes (Vβ8.2/7/2 in mice and Vβ11 in humans) (1–20, 24–26). The semi-invariant TCR on type I NKT cells preferentially binds to CD1d via its α-chain (3, 6, 15, 25).
Type II NKT cells constitute a minor subset in mice, but are more predominant in humans (18, 27). Most type II NKT cells do not recognize α-linked glycolipids, but rather respond to sulphatide, a self-antigen that occurs naturally on cell membranes in the central nervous system (myelin sheath), pancreas, kidney, and liver. Sulphatide-reactive type II NKT cells may protect from autoimmune diseases by down-regulation of inflammatory responses elicited by type I NKT cells (28, 29). In contrast, non-sulphatide-reactive type II NKT cells may be pathogenic in other diseases, such as ulcerative colitis (UC) (30). Sulphatide-reactive type II NKT cells express oligoclonal TCRs and express a limited number of Vα and Vβ chains. The antigen specificity of type II NKT cells appears to be conferred by their surface TCR Vβ-chain (31).
CD1d and NKT Cell-Mediated Antimicrobial Immunity
Antimicrobial defense may be mediated by extensive cross-regulation between CD1d, NKT cells, and microbes that function predominantly at mucosal surfaces (32–34). The display of microbes at mucosal surfaces, mainly during early postnatal development, controls NKT cell trafficking and function in the intestine, lung, and intestine. Microbial recognition at these sites determines the susceptibility to NKT cell-mediated inflammatory disorders. Conversely, CD1d expression controls the composition of the intestinal microbiota. Whereas microbiota reduce the number and activity of type I NKT cells at mucosal sites, an elevated number and function of type I NKT cells may be stimulated by microbiota in peripheral tissues (32). Thus, crosstalk between microbiota and type I NKT cells influences mucosal homeostasis and its dysregulation in a bidirectional manner in inflammatory disorders.
In human inflammatory bowel disease (IBD) and infectious hepatitis, type II NKT cells are causal to inflammation (10). In contrast, intestinal inflammation in oxazolone-induced colitis, a mouse model of human UC, is dependent on CD1d and type I NKT cells that express IL-17 and secrete IL-13 (10, 35). Thus, intestinal microbiota influence pathogenic responses in NKT cell-mediated intestinal inflammation. The outcome of these responses depends on the time of microbial exposure, NKT cell subset(s) involved, nature of microbial lipid antigens recognized, and type of APC that presents CD1d-restricted antigens to NKT cells. CD1d-restricted interactions of type I NKT cells with intestinal epithelial cells (IECs) promote IL-10 secretion and mucosal homeostasis, while CD1d-dependent interactions with bone marrow-derived APCs contribute to intestinal inflammation (36). Further experimentation may reveal whether these various responses result from the expression of different costimulatory molecules by IECs and professional APCs or whether cell-type-specific differences in CD1d trafficking and lipid acquisition contribute to this outcome. The central questions that need to be addressed are: (1) how do specific microbes control mucosal NKT cell abundance and function and determine health vs. disease, (2) what are the pathways of antigen-dependent and cytokine-dependent activation in NKT cells, and (3) do specific alterations in intestinal microbiota (e.g., in patients with IBD) (37) contribute to intestinal inflammation by the differential homing, proliferation, and activation of NKT cell subsets.
Like the intestine, the lung is a site of interaction between commensal microbiota and mucosal NKT cells. Insufficient microbial colonization during neonatal life leads to increased quantities and environmental sensitivity of type I NKT cells in lungs leading to susceptibility to asthma. This notion is supported by the result that exposure to antibiotics during early life but not late life enhances susceptibility to asthma in mice (38). In addition, elevated numbers of type I NKT cells are found in the lungs of germ-free mice. The latter finding requires the hypermethylation of the Cxcl16 chemokine gene and increased expression of the CXCL16 chemokine protein, which binds to the CXCR6 cognate chemokine receptor found on NKT cells (39). These alterations are associated with increased airway resistance, eosinophil infiltration, and proinflammatory cytokine production during ovalbumin (OVA)-induced asthma in mice (39). Thus, the development, migration, and function of type I NKT cells at mucosal surfaces may be influenced by commensal microbiota (6).
Tracking of T Cells In vivo by Intravital Cellular Imaging
Studies of NKT cell-mediated inflammation at different mucosal surfaces (e.g., intestine, lung, colon) illustrate that increased understanding of the mechanisms of differential recirculation, migration, proliferation, and activation of NKT cells during pathological responses requires the use of a technology that enables the visualization of these NKT cell events in real-time in vivo. The technique of two-photon (2P) microscopy coupled with intravital imaging enables one to track the location, movement, and interactions of cells (40–44). As such, 2P microscopy has improved our knowledge of T cell–DC and T cell–B cell interactions by recording how such cells function in resting tissue and undergo interaction, information exchange, and response to pathogens (40–43, 45). This methodology has also provided much new information about cellular pathways that arise during disease progression by illustrating the outcome of specific events in real-time (40–44). Intravital imaging and quantification of cell dynamics in vivo requires the use of fluorescently tagged proteins that are expressed transgenically in a cell-type-specific fashion to monitor the migration of single cells from blood vessels to tissues at a maximum tissue depth of 300–400 μm.
Initial studies on T cell–APC interactions during the establishment of peripheral tolerance were conducted with conventional CD4+ T cells and APCs in the LN and spleen, and showed that the time of contact between CD4+ T cells and APCs may vary from long-lived (days) to short-lived (a few hours) (40, 43). This difference in time of T cell–APC contact may influence the relative capacity of an agent administered in vivo to treat a given disease and induce (pre-disease) or restore (post-disease) immune tolerance. For example, CTLA-4 and PD-1 inhibitory receptors on Teff or regulatory T (Treg) cells can suppress immune responses by limiting the times of effective interactions of T cells with DCs (44, 46, 47). During chronic inflammation, cytokine delivery requires long-term T cell–APC contacts. However, only a relatively small number of cytokine molecules may be secreted at a low antigen concentration (43, 44, 46, 47). At a high concentration of antigen, the duration of T cell–APC contacts may be sufficiently long to elicit a chronic inflammatory response. Protection against inflammation is more likely to occur at a significantly lower antigen concentration (43). Further experimentation is required to analyze the effects of antigen concentration, time of cytokine production by CD4+ T cells in high vs. low antigen concentration tissue environments, and whether effector cytokines function locally at a particular site or are transported to other distal sites. Nonetheless, the results reported for the tracking and function of conventional CD4+ T cells in vivo have facilitated analyses of the migration and function of NKT cells in vivo.
Imaging of NKT Cell Recirculation, Migration, and Activation
T cell receptor signal strength may determine the cytokine secretion profiles of T cells in a reciprocal manner. That is, the binding of TCRs of type I NKT cells to their antigen ligands can regulate the activity of TCRs on type II NKT cells. In turn, the binding of TCRs of type II NKT cells to their antigen ligands can regulate the activity of TCRs on type I NKT cells. Understanding the basis of how this cross-regulation of NKT cell activation occurs is crucial to develop better strategies to prevent microbial infection (2, 8–12, 48–52).
Such studies require a suitable animal model in which to track NKT cell recirculation and migration in vivo. For this reason, heterozygous mice were generated in which the green fluorescent protein (GFP) gene was knocked into a lineage-specific gene enabling certain leukocytes to be fluorescently labeled (53). In mice that express GFP integrated into the Cxcr6 chemokine receptor gene (Cxcr6gfp/+ mice), type I NKT cells traffic to, and become quite abundant in the liver (20–30% of lymphocytes). However, NKT cell migration within the liver is arrested following interaction with Kupffer cells. The latter interaction occurs within minutes following lipid antigen injection (54–58). In addition, both IL-12 and IL-18 proinflammatory cytokines induced following bacterial infection that suppresses type I NKT cell motility in liver sinusoids of Cxcr6gfp/+ mice via a CD1d-independent mechanism. This block in NKT cell movement is evident within 1 h after exposure to the cytokines and precedes NKT cell activation. Further antigen ligation stabilizes an immune synapse formed between NKT cells and interacting APCs. This synapse potentiates LFA-1/ICAM-1 interactions that enable activated type I NKT cells to remain in the liver. Thus, activated type I NKT cells recirculate less than activated conventional CD4+ T cells (59). Identification of the patterns and kinetics of recirculation of type I and type II mouse NKT cells as well as the patterns and kinetics of human type I and type II NKT cells await further study.
A future goal of studies of human NKT cells is to identify their functional roles in health and disease (1). Determination of how subsets of human NKT cells migrate and recirculate in vivo may advance our understanding of the biology and mechanisms of cellular interaction of different human NKT cells with APCs. Current investigations are being performed in two animal models. First, Cxcr6gfp/+ mice are being used to monitor human NKT cell trafficking, localization, and activation in vivo (56). Second, the kinetics and dynamics of human CD1d (hCD1d)-restricted NKT cell interactions are being analyzed in hCD1d knock-in mice that express hCD1d in place of mCD1d (59). Subpopulations of mouse type I NKT cells that are similar to human type I NKT cells in phenotype (mouse Vβ8+, human Vβ11 homolog+, CD4low), tissue distribution, and function (anti-tumor activity) are present in hCD1d knock-in mice. The latter mice serve to model how a lipid antigen induces the migration and function of hCD1d-restricted type I NKT cells and type II NKT cells in vivo (59–62). If type I and type II human NKT cells can be differentially activated or inhibited in vivo, this may facilitate the design of new immunotherapeutic protocols in the treatment and prevention of infectious diseases.
Additional imaging studies are required to delineate whether, in addition to NKT cells regulation at mucosal surfaces, commensal bacteria also regulate NKT cells at other sites, e.g., the skin where microbiota are in close contact with NKT cells and CD1a-restricted, lipid-reactive T cells (63–65). Future work may also establish potential species-specific and antigen-specific effects of microbiota on NKT cells and the roles of viruses and fungi in this process. Finally, it is of major clinical interest to develop therapeutic strategies that may induce changes in the function of type I NKT cells at mucosal surfaces that will promote and/or preserve mucosal homeostasis and antimicrobial immunity.
Conflict of Interest Statement
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
8. Lindau D, Gielen P, Kroesen M, Wesseling P, Adema GJ. The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells. Immunology (2012) 138:105–15. doi:10.1111/imm.12036
9. Simoni Y, Diana J, Ghazarian L, Beaudoin L, Lehuen A. Therapeutic manipulation of natural killer (NK) T cells in autoimmunity: are we close to reality? Clin Exp Immunol (2012) 171:8–19. doi:10.1111/j.1365-2249.2012.04625.x
12. Viale R, Ware R, Maricic I, Chaturvedi V, Kumar V. NKT cell subsets can exert opposing effects in autoimmunity, tumor surveillance and inflammation. Curr Immunol Rev (2012) 8:1–10. doi:10.2174/157339512804806224
13. Godfrey DI, Pellicci DG, Patel O, Kjer-Nielsen L, McCluskey J, Rossjohn J. Antigen recognition by CD1d-restricted NKT T cell receptors. Semin Immunol (2009) 22:61–7. doi:10.1016/j.smim.2009.10.004
14. Crowe NY, Uldrich AP, Kyparissoudis K, Hammond KJ, Hayakawa Y, Sidobre S, et al. Glycolipid antigen drives rapid expansion and sustained cytokine production by NKT cells. J Immunol (2003) 171:4020–7. doi:10.4049/jimmunol.171.8.4020
15. Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K, et al. CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. Science (1997) 278:1626–9. doi:10.1126/science.278.5343.1626
16. Snyder-Cappione JE, Tincati C, Eccles-James IG, Cappione AJ, Ndhlovu LC, Koth LL, et al. A comprehensive ex vivo functional analysis of human NKT cells reveals production of MIP1-alpha and MIP1-beta, a lack of IL-17, and a Th1-bias in males. PLoS One (2010) 5:e15412. doi:10.1371/journal.pone.0015412
17. Jahng AW, Maricic I, Pedersen B, Burdin N, Naidenko O, Kronenberg M, et al. Activation of natural killer T cells potentiates or prevents experimental autoimmune encephalomyelitis. J Exp Med (2001) 194:1789–99. doi:10.1084/jem.194.12.1789
18. Arrenberg P, Halder R, Kumar V. Cross-regulation between distinct natural killer T cell subsets influences immune response to self and foreign antigens. J Cell Physiol (2009) 218:246–50. doi:10.1002/jcp.21597
19. Benlagha K, Weiss A, Beavis A, Teyton L, Bendelac A. In vivo identification of glycolipid antigen-specific T cells using fluorescent CD1d tetramers. J Exp Med (2000) 192:1895–903. doi:10.1084/jem.191.11.1895
20. Chiu YH, Jayawardena J, Weiss A, Lee D, Park SH, Dautry-Varsat A, et al. Distinct subsets of CD1d-restricted T cells recognize self-antigens loaded in different cellular compartments. J Exp Med (1999) 189:103–10. doi:10.1084/jem.189.1.103
21. Matsuda JL, Naidenko OV, Gapin L, Nakayama T, Taniguchi M, Wang CR, et al. Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers. J Exp Med (2000) 192:741–54. doi:10.1084/jem.192.5.741
22. Cardell S, Tangri S, Chan S, Kronenberg M, Benoist C, Mathis D. CD1-restricted CD4+ T cells in major histocompatibility complex class II-deficient mice. J Exp Med (1995) 182:993–1004. doi:10.1084/jem.182.4.993
24. Park SH, Weiss A, Benlagha K, Kyin T, Teyton L, Bendelac A. The mouse CD1d-restricted repertoire is dominated by a few autoreactive T cell receptor families. J Exp Med (2001) 193:893–904. doi:10.1084/jem.193.8.893
25. Exley MA, Tahir SM, Cheng O, Shaulov A, Joyce R, Avigan D, et al. A major fraction of human bone marrow lymphocytes are Th2-like CD1d-reactive T cells that can suppress mixed lymphocyte responses. J Immunol (2001) 167:5531–44. doi:10.4049/jimmunol.167.10.5531
26. Jahng A, Maricic I, Aguilera C, Cardell S, Halder RC, Kumar V. Prevention of autoimmunity by targeting a distinct, noninvariant CD1d-reactive T cell population reactive to sulfatide. J Exp Med (2004) 199:947–57. doi:10.1084/jem.20031389
27. Arrenberg P, Halder R, Dai Y, Maricic I, Kumar V. Oligoclonality and innate-like features in the TCR repertoire of type II NKT cells reactive to a beta-linked self-glycolipid. Proc Natl Acad Sci U S A (2010) 107:10984–9. doi:10.1073/pnas.1000576107
28. Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S, et al. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest (2001) 13:1490–7.
29. Girardi E, Maricic I, Wang J, Mac TT, Iyer P, Kumar V, et al. Type II natural killer T cells use features of both innate-like and conventional T cells to recognize sulfatide self antigens. Nat Immunol (2012) 13:851–6. doi:10.1038/ni.2371
30. Zajonc DM, Maricic I, Wu D, Halder R, Roy K, Wong CH, et al. Structural basis for CD1d presentation of a sulfatide derived from myelin and its implications for autoimmunity. J Exp Med (2005) 202:1517–26. doi:10.1084/jem.20051625
31. Bai L, Picard D, Anderson B, Chaudary V, Luoma A, Jabri B, et al. The majority of CD1d-sulfatide-specific T cells in human blood use a semi-invariant Vd1 TCR. Eur J Immunol (2012) 42:2505–10. doi:10.1002/eji.201242531
35. Zeissig S, Kaser A, Dougan SK, Nieuwenhuis EE, Blumberg RS. Role of NKT cells in the digestive system. III. Role of NKT cells in intestinal immunity. Am J Physiol Gastrointest Liver Physiol (2007) 293:G1101–5. doi:10.1152/ajpgi.00342.2007
36. Heller F, Fuss IJ, Nieuwenhuis EE, Blumberg RS, Strober W. Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NKT cells. Immunity (2002) 17:629–38. doi:10.1016/S1074-7613(02)00453-3
38. Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A (2007) 104:13780–5. doi:10.1073/pnas.0706625104
39. Russell SL, Gold MJ, Hartmann M, Willing BP, Thorson L, Wlodarska M, et al. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO Rep (2012) 13:440–7. doi:10.1038/embor.2012.32
43. Egen JG, Rotfuchs AG, Feng CG, Horwitz MA, Sher A, Germain RG. Intravital imaging reveals limited antigen presentation and T cell effector function in mycobacterial granulomas. Immunity (2011) 34:807–19. doi:10.1016/j.immuni.2011.03.022
45. Olszak T, An D, Zeissig S, Vera MP, Richter J, Franke A, et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science (2012) 336:489–93. doi:10.1126/science.1219328
47. Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, et al. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol (2009) 10:1185–92. doi:10.1038/ni.1790
48. Hugues S, Fetler L, Bonifaz L, Helft J, Amblard F, Amigorena S. Distinct T cell dynamics in lymph nodes during the induction of tolerance and immunity. Nat Immunol (2004) 5:1235–42. doi:10.1038/ni1134
49. Cohen NR, Brennan PJ, Shay T, Watts GF, Brigl M, Kang J, et al. Shared and distinct transcriptional program underlie the hybrid nature of iNKT cells. Nat Immunol (2013) 14:90–100. doi:10.1038/ni.2490
52. Halder RC, Aguilera C, Maricic I, Kumar V. Type II NKT cell-mediated anergy induction n type I NKT cells prevents inflammatory liver disease. J Clin Invest (2007) 117:2302–12. doi:10.1172/JCI31602
53. Spada FM, Grant EP, Peters PJ, Sugita M, Melián A, Leslie DS, et al. Self-recognition of Cd1 by γ/δ T cells: implications for innate immunity. J Exp Med (2000) 191:937–48. doi:10.1084/jem.191.6.937
57. Geissmann F, Cameron TO, Sidobre S, Manlongat N, Kronenberg M, Briskin MJ, et al. Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids. PLoS Biol (2005) 3:e113. doi:10.1371/journal.pbio.0030113
58. Velázquez P, Cameron TO, Kinjo Y, Nagarajan N, Kronenberg M, Dustin ML. Activation by innate cytokines or microbial antigens can cause arrest of natural killer T cell patrolling of liver sinusoids. J Immunol (2008) 180:2024–8. doi:10.4049/jimmunol.180.4.2024
59. Thomas SY, Scanlon ST, Griewank KG, Constantinides MG, Savage AK, Barr KA, et al. PLZF induces an intravascular surveillance program mediated by long-lived LFA-1/ICAM-1 interactions. J Exp Med (2011) 208:1179–88. doi:10.1084/jem.20102630
60. Wen X, Rao P, Carreno LJ, Kim S, Lawrenczyk A, Porcelli SA, et al. Human CD1d knock-in mouse model demonstrates potent antitumor potential of human CD1d-restricted invariant natural killer cells. Proc Natl Acad Sci U S A (2013) 110:2963–8. doi:10.1073/pnas.1300200110
61. Giaccone G, Punt CJ, Ando Y, Ruijter R, Nishi N, Peters M, et al. A phase I study of the natural killer T-cell ligand α-galactosylceramide (KRN7000) in patients with solid tumors. Clin Cancer Res (2002) 8:3702–9.
62. Nieda M, Okai M, Tazbirkova A, Lin H, Yamaura A, Ide K, et al. Therapeutic activation of Vα24+ Vβ11+ NKT cells in human subjects results in highly coordinated secondary activation of acquired and innate immunity. Blood (2004) 103:383–9. doi:10.1182/blood-2003-04-1155
63. Chang DH, Osman K, Connolly J, Kukreja A, Krasovsky J, Pack M, et al. Sustained expansion of NKT cells and antigen-specific T cells after injection of α-galactosyl-ceramide loaded mature dendritic cells in cancer patients. J Exp Med (2005) 201:1503–17. doi:10.1084/jem.20042592
Keywords: NKT cells, anti-microbial immunity, immunoregulation, in vivo imaging, immunotherapy
Citation: Delovitch TL (2015) Imaging of NKT cell recirculation and tissue migration during antimicrobial immunity. Front. Immunol. 6:356. doi: 10.3389/fimmu.2015.00356
Received: 02 February 2015; Accepted: 30 June 2015;
Published: 14 July 2015
Edited by:Thierry Mallevaey, University of Toronto, Canada
Reviewed by:Kristin Hogquist, University of Minnesota, USA
Paul Kubes, University of Calgary, Canada
Irah L. King, McGill University, Canada
Copyright: © 2015 Delovitch. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Terry L. Delovitch, email@example.com