Analyze Diet
Viruses2024; 16(10); doi: 10.3390/v16101514

Characterization of Nasal Mucosal T Cells in Horses and Their Response to Equine Herpesvirus Type 1.

Abstract: Equine herpesvirus type 1 (EHV-1) enters through the upper respiratory tract (URT). Mucosal immunity at the URT is crucial in limiting viral infection and morbidity. Here, intranasal immune cells were collected from horses (n = 15) during an experimental EHV-1 infection. CD4+ and CD8+ T cells were the major intranasal cell populations before infection and increased significantly by day six and fourteen post-infection, respectively. Nasal mucosal T cells were further characterized in healthy horses. Compared to peripheral blood mononuclear cells (PBMC), mucosal CD8+ T-cell percentages were elevated, while CD4+ T-cell percentages were similar. A small population of CD4+CD8+ T cells was also recovered from mucosal samples. Within the URT tissue, CD4+ cells predominantly accumulated in the epithelial layer, while most CD8+ cells resided deeper in the mucosa or the submucosa below the basement membrane. In vitro stimulation of mucosal cells from healthy horses with (n = 5) or without (n = 5) peripheral T-cell immunity against EHV-1 induced IFN-γ production in nasal T cells upon polyclonal stimulation. However, after EHV-1 re-stimulation, mucosal T cells failed to respond with IFN-γ. This work provided the first characterization of mucosal T-cell phenotypes and functions in the URT of healthy horses and during EHV-1 infection.
Publication Date: 2024-09-25 PubMed ID: 39459849PubMed Central: PMC11512333DOI: 10.3390/v16101514Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This study examined the nature of T cells (a type of white blood cell that plays a key role in the immune response) located in the nasal passages of horses, and how they respond to Equine Herpesvirus Type 1 (EHV-1), a virus that infects the upper respiratory tract of horses.

Introduction and Methodology

  • The researchers were primarily interested in understanding the role of the body’s mucosal immunity, i.e., the immune response at the mucosal level, in limiting the infection and adverse effects of EHV-1. EHV-1 enters through the upper respiratory tract, and thus studying the immune cells of this region is vital.
  • The study involved collecting intranasal immune cells from 15 horses during an experimental EHV-1 infection. The researchers paid specific attention to two major intranasal cell types, CD4 and CD8 T cells.

Findings

  • The CD4 and CD8 T cells were found to be the principal intranasal cell populations before infection. Notably, these cell populations significantly increased by the sixth day (for CD4 cells) and fourteenth day (for CD8 cells) post-infection.
  • The study went further to characterize these nasal mucosal T cells in healthy horses. Relative to peripheral blood mononuclear cells (PBMC – a type of blood cell critical to immunity), the percentages of mucosal CD8 T cells were found to be higher, while those of CD4 T cells remained similar.
  • Interestingly, a small population of CD4CD8 T cells was also recovered from the mucosal samples. Different subsets of T cells were observed to occupy different regions within the upper respiratory tract tissue. Specifically, CD4 cells mainly accumulated in the epithelial layer, while most CD8 cells resided deeper in the mucosa or submucosa (a layer below the mucosa).
  • When the researchers stimulated mucosal cells from healthy horses (with or without peripheral T-cell immunity against EHV-1), the nasal T cells produced IFN-γ (a type of protein) upon general (polyclonal) stimulation. However, upon re-stimulation with EHV-1, the mucosal T cells did not respond with IFN-γ production.

Conclusion

  • The findings of this study provide the first description of mucosal T-cell phenotypes (observable characteristics resulting from interaction of their genetic make-up and environment) and their functions in healthy horses, as well as during a EHV-1 infection.
  • Understanding these cellular responses to EHV-1 could potentially inform the design of improved vaccines or treatments for this infection in horses.

Cite This Article

APA
Holmes CM, Wagner B. (2024). Characterization of Nasal Mucosal T Cells in Horses and Their Response to Equine Herpesvirus Type 1. Viruses, 16(10). https://doi.org/10.3390/v16101514

Publication

ISSN: 1999-4915
NlmUniqueID: 101509722
Country: Switzerland
Language: English
Volume: 16
Issue: 10

Researcher Affiliations

Holmes, Camille M
  • Department of Population Medicine and Diagnostic Science, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
Wagner, Bettina
  • Department of Population Medicine and Diagnostic Science, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.

MeSH Terms

  • Animals
  • Horses / immunology
  • Herpesvirus 1, Equid / immunology
  • Nasal Mucosa / virology
  • Nasal Mucosa / immunology
  • Herpesviridae Infections / immunology
  • Herpesviridae Infections / veterinary
  • Herpesviridae Infections / virology
  • CD8-Positive T-Lymphocytes / immunology
  • Horse Diseases / immunology
  • Horse Diseases / virology
  • CD4-Positive T-Lymphocytes / immunology
  • Immunity, Mucosal
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / virology
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • T-Lymphocytes / immunology
  • Female

Grant Funding

  • Young Investigator Award / American Quarter Horse Foundation
  • N/A / Harry M. Zweig Memorial Fund for Equine Research at Cornell University

Conflict of Interest Statement

The authors declare no conflicts of interest.

References

This article includes 84 references
  1. Fournier M, Lebargy F, Ladurie F.L.R., Lenormand E, Pariente R. Intraepithelial T-Lymphocyte Subsets in the Airways of Normal Subjects and of Patients with Chronic Bronchitis. Am. Rev. Respir. Dis. 1989;140:737–742.
    doi: 10.1164/ajrccm/140.3.737pubmed: 2528933google scholar: lookup
  2. Snyder M.E., Farber D.L.. Human Lung Tissue Resident Memory T Cells in Health and Disease. Curr. Opin. Immunol. 2019;59:101–108.
    doi: 10.1016/j.coi.2019.05.011pmc: PMC6774897pubmed: 31265968google scholar: lookup
  3. Bienenstock J., McDermott M.R.. Bronchus- and Nasal-associated Lymphoid Tissues. Immunol. Rev. 2005;206:22–31.
  4. Buggert M., Price D.A., Mackay L.K., Betts M.R.. Human Circulating and Tissue-Resident Memory CD8+ T Cells. Nat. Immunol. 2023;24:1076–1086.
    doi: 10.1038/s41590-023-01538-6pubmed: 37349380google scholar: lookup
  5. Cheroutre H., Huang Y. Crosstalk Between Adaptive and Innate Immune Cells Leads to High Quality Immune Protection at the Mucosal Borders. In: Katsikis P.D., Schoenberger S.P., Pulendran B., editors. Crossroads Between Innate and Adaptive Immunity IV. Volume 785. Advances in Experimental Medicine and Biology; Springer; New York, NY, USA: 2013. pp. 43–47.
    pmc: PMC3913074pubmed: 23456836
  6. Yunis J., Short K.R., Yu D. Severe Respiratory Viral Infections: T-Cell Functions Diverging from Immunity to Inflammation. Trends Microbiol. 2023;31:644–656.
    doi: 10.1016/j.tim.2022.12.008pmc: PMC9829516pubmed: 36635162google scholar: lookup
  7. Gilkerson J.R., Bailey K.E., Diaz-Méndez A., Hartley C.A.. Update on Viral Diseases of the Equine Respiratory Tract. Vet. Clin. N. Am. Equine Pract. 2015;31:91–104.
    doi: 10.1016/j.cveq.2014.11.007pubmed: 25648568google scholar: lookup
  8. Allen G. Respiratory Infections by Equine Herpesvirus Types 1 and 4. In: Lekeux P., editor. Equine Respiratory Diseases. International Veterinary Information Service; Ithaca, NY, USA: 2002.
  9. Edington N., Welch H.M., Griffiths L. The Prevalence of Latent Equid Herpesviruses in the Tissues of 40 Abattoir Horses. Equine Vet. J. 1994;26:140–142.
  10. Allen G.P.. Risk Factors for Development of Neurologic Disease after Experimental Exposure to Equine Herpesvirus-1 in Horses. Am. J. Vet. Res. 2008;69:1595–1600.
    doi: 10.2460/ajvr.69.12.1595pubmed: 19046006google scholar: lookup
  11. Patel J.R., Edington N., Mumford J.A.. Variation in Cellular Tropism between Isolates of Equine Herpesvirus-1 in Foals. Arch. Virol. 1982;74:41–51.
    doi: 10.1007/BF01320781pubmed: 6297429google scholar: lookup
  12. Kydd J.H., Smith K.C., Hannant D., Livesay G.J., Mumford J.A.. Distribution of Equid Herpesvirus-1 (EHV-1) in Respiratory Tract Associated Lymphoid Tissue: Implications for Cellular Immunity. Equine Vet. J. 1994;26:470–473.
  13. Baghi H.B., Nauwynck H.J.. Impact of Equine Herpesvirus Type 1 (EHV-1) Infection on the Migration of Monocytic Cells through Equine Nasal Mucosa. Comp. Immunol. Microbiol. Infect. Dis. 2014;37:321–329.
    doi: 10.1016/j.cimid.2014.09.004pubmed: 25456193google scholar: lookup
  14. Wimer C.L., Schnabel C.L., Perkins G., Babasyan S., Freer H., Stout A.E., Rollins A., Osterrieder N., Goodman L.B., Glaser A.. The Deletion of the ORF1 and ORF71 Genes Reduces Virulence of the Neuropathogenic EHV-1 Strain Ab4 without Compromising Host Immunity in Horses. PLoS ONE 2018;13:e0206679.
  15. Schnabel C.L., Wimer C.L., Perkins G., Babasyan S., Freer H., Watts C., Rollins A., Osterrieder N., Wagner B.. Deletion of the ORF2 Gene of the Neuropathogenic Equine Herpesvirus Type 1 Strain Ab4 Reduces Virulence While Maintaining Strong Immunogenicity. BMC Vet. Res. 2018;14:245.
    doi: 10.1186/s12917-018-1563-4pmc: PMC6106926pubmed: 30134896google scholar: lookup
  16. Laval K., Favoreel H.W., Nauwynck H.J.. Equine Herpesvirus Type 1 Replication Is Delayed in CD172a+ Monocytic Cells and Controlled by Histone Deacetylases. J. Gen. Virol. 2015;96:118–130.
    doi: 10.1099/vir.0.067363-0pubmed: 25239765google scholar: lookup
  17. Osterrieder N., Van de Walle G.R.. Pathogenic Potential of Equine Alphaherpesviruses: The Importance of the Mononuclear Cell Compartment in Disease Outcome. Vet. Microbiol. 2010;143:21–28.
    doi: 10.1016/j.vetmic.2010.02.010pubmed: 20202764google scholar: lookup
  18. Kydd J.H., Townsend H.G.G., Hannant D.. The Equine Immune Response to Equine Herpesvirus-1: The Virus and Its Vaccines. Vet. Immunol. Immunopathol. 2006;111:15–30.
    doi: 10.1016/j.vetimm.2006.01.005pubmed: 16476492google scholar: lookup
  19. Edington N., Bridges C.G., Huckle A.. Experimental Reactivation of Equid Herpesvirus 1 (EHV 1) Following the Administration of Corticosteroids. Equine Vet. J. 1985;17:369–372.
  20. Pusterla N., David Wilson W., Madigan J.E., Ferraro G.L.. Equine Herpesvirus-1 Myeloencephalopathy: A Review of Recent Developments. Vet. J. 2009;180:279–289.
    doi: 10.1016/j.tvjl.2008.08.004pubmed: 18805030google scholar: lookup
  21. Edington N., Smyth B., Griffiths L.. The Role of Endothelial Cell Infection in the Endometrium, Placenta and Foetus of Equid Herpesvirus 1 (EHV-1) Abortions. J. Comp. Pathol. 1991;104:379–387.
    doi: 10.1016/S0021-9975(08)80148-Xpubmed: 1651960google scholar: lookup
  22. Smith K.C., Mumford J.A., Lakhani K.. A Comparison of Equid Herpesvirus-1 (EHV-1) Vascular Lesions in the Early versus Late Pregnant Equine Uterus. J. Comp. Pathol. 1996;114:231–247.
    doi: 10.1016/S0021-9975(96)80045-4pubmed: 8762581google scholar: lookup
  23. Reed S.M., Toribio R.E.. Equine Herpesvirus 1 and 4. Vet. Clin. N. Am. Equine Pract. 2004;20:631–642.
    doi: 10.1016/j.cveq.2004.09.001pubmed: 15519823google scholar: lookup
  24. Schnabel C.L., Babasyan S., Rollins A., Freer H., Wimer C.L., Perkins G.A., Raza F., Osterrieder N., Wagner B.. An Equine Herpesvirus Type 1 (EHV-1) Ab4 Open Reading Frame 2 Deletion Mutant Provides Immunity and Protection from EHV-1 Infection and Disease. J. Virol. 2019;93:e01011-19.
    doi: 10.1128/JVI.01011-19pmc: PMC6819910pubmed: 31462575google scholar: lookup
  25. Holmes C.M., Babasyan S., Eady N., Schnabel C.L., Wagner B.. Immune Horses Rapidly Increase Antileukoproteinase and Lack Type I Interferon Secretion during Mucosal Innate Immune Responses against Equine Herpesvirus Type 1. Microbiol. Spectr. 2024:e01092-24.
    doi: 10.1128/spectrum.01092-24pmc: PMC11448092pubmed: 39162558google scholar: lookup
  26. Schnabel C.L., Wemette M., Babasyan S., Freer H., Baldwin C., Wagner B.. C-C Motif Chemokine Ligand (CCL) Production in Equine Peripheral Blood Mononuclear Cells Identified by Newly Generated Monoclonal Antibodies. Vet. Immunol. Immunopathol. 2018;204:28–39.
    doi: 10.1016/j.vetimm.2018.09.003pubmed: 30596378google scholar: lookup
  27. Melchjorsen J., Sørensen L.N., Paludan S.R.. Expression and Function of Chemokines during Viral Infections: From Molecular Mechanisms to in Vivo Function. J. Leukoc. Biol. 2003;74:331–343.
    doi: 10.1189/jlb.1102577pmc: PMC7166880pubmed: 12949236google scholar: lookup
  28. Breathnach C.C., Yeargan M.R., Timoney J.F., Allen G.P.. Detection of Equine Herpesvirus-Specific Effector and Memory Cytotoxic Immunity in the Equine Upper Respiratory Tract. Vet. Immunol. Immunopathol. 2006;111:117–125.
    doi: 10.1016/j.vetimm.2006.01.014pubmed: 16472871google scholar: lookup
  29. Eady N., Holmes C.M., Schnabel C.L., Babasyan S., Wagner B.. Equine Herpesvirus Type-1 (EHV-1) Replication at the Upper Respiratory Entry Site Is Inhibited by Neutralizing EHV-1 Specific IgG1 and IgG4/7 Mucosal Antibodies. J. Virol. 2024;98:e00250-24.
    doi: 10.1128/jvi.00250-24pmc: PMC11237562pubmed: 38742875google scholar: lookup
  30. Zhao J., Poelaert K.C.K., Van Cleemput J., Nauwynck H.J.. CCL2 and CCL5 Driven Attraction of CD172a+ Monocytic Cells during an Equine Herpesvirus Type 1 (EHV-1) Infection in Equine Nasal Mucosa and the Impact of Two Migration Inhibitors, Rosiglitazone (RSG) and Quinacrine (QC). Vet. Res. 2017;48:14.
    doi: 10.1186/s13567-017-0419-4pmc: PMC5327560pubmed: 28241864google scholar: lookup
  31. Poelaert K.C.K., Van Cleemput J., Laval K., Favoreel H.W., Couck L., Van den Broeck W., Azab W., Nauwynck H.J.. Equine Herpesvirus 1 Bridles T Lymphocytes To Reach Its Target Organs. J. Virol. 2019;93:e02098-18.
    doi: 10.1128/JVI.02098-18pmc: PMC6430527pubmed: 30651370google scholar: lookup
  32. Gryspeerdt A.C., Vandekerckhove A.P., Baghi H.B., Van de Walle G.R., Nauwynck H.J.. Expression of Late Viral Proteins Is Restricted in Nasal Mucosal Leucocytes but Not in Epithelial Cells during Early-Stage Equine Herpes Virus-1 Infection. Vet. J. 2012;193:576–578.
    doi: 10.1016/j.tvjl.2012.01.022pubmed: 22425309google scholar: lookup
  33. Vandekerckhove A.P., Glorieux S., Gryspeerdt A.C., Steukers L., Duchateau L., Osterrieder N., Van de Walle G.R., Nauwynck H.J.. Replication Kinetics of Neurovirulent versus Non-Neurovirulent Equine Herpesvirus Type 1 Strains in Equine Nasal Mucosal Explants. J. Gen. Virol. 2010;91:2019–2028.
    doi: 10.1099/vir.0.019257-0pubmed: 20427565google scholar: lookup
  34. Perkins G., Babasyan S., Stout A.E., Freer H., Rollins A., Wimer C.L., Wagner B.. Intranasal IgG4/7 Antibody Responses Protect Horses against Equid Herpesvirus-1 (EHV-1) Infection Including Nasal Virus Shedding and Cell-Associated Viremia. Virology 2019;531:219–232.
    doi: 10.1016/j.virol.2019.03.014pubmed: 30928700google scholar: lookup
  35. O’Neill T., Kydd J.H., Allen G.P., Wattrang E., Mumford J.A., Hannant D.. Determination of Equid Herpesvirus 1-Specific, CD8+, Cytotoxic T Lymphocyte Precursor Frequencies in Ponies. Vet. Immunol. Immunopathol. 1999;70:43–54.
    doi: 10.1016/S0165-2427(99)00037-9pubmed: 10507286google scholar: lookup
  36. Kydd J.H., Wattrang E., Hannant D.. Pre-Infection Frequencies of Equine Herpesvirus-1 Specific, Cytotoxic T Lymphocytes Correlate with Protection against Abortion Following Experimental Infection of Pregnant Mares. Vet. Immunol. Immunopathol. 2003;96:207–217.
    doi: 10.1016/j.vetimm.2003.08.004pubmed: 14592733google scholar: lookup
  37. Bridges C.G., Edington N.. Genetic Restriction of Cytolysis during Equid Herpesvirus 1 Subtype 2 Infection. Clin. Exp. Immunol. 1987;70:276–282.
    pmc: PMC1542070pubmed: 2827921
  38. Allen G., Yeargan M., Costa L.R., Cross R.. Major Histocompatibility Complex Class I-Restricted Cytotoxic T-Lymphocyte Responses in Horses Infected with Equine Herpesvirus 1. J. Virol. 1995;69:606–612.
    doi: 10.1128/jvi.69.1.606-612.1995pmc: PMC188619pubmed: 7983765google scholar: lookup
  39. Paillot R., Ellis S., Daly J., Audonnet J., Minke J., Davispoynter N., Hannant D., Kydd J.. Characterisation of CTL and IFN-γ Synthesis in Ponies Following Vaccination with a NYVAC-Based Construct Coding for EHV-1 Immediate Early Gene, Followed by Challenge Infection. Vaccine 2006;24:1490–1500.
    doi: 10.1016/j.vaccine.2005.10.019pubmed: 16269205google scholar: lookup
  40. Paillot R., Daly J.M., Luce R., Montesso F., Davis-Poynter N., Hannant D., Kydd J.H.. Frequency and Phenotype of EHV-1 Specific, IFN-γ Synthesising Lymphocytes in Ponies: The Effects of Age, Pregnancy and Infection. Dev. Comp. Immunol. 2007;31:202–214.
    doi: 10.1016/j.dci.2006.05.010pubmed: 16824599google scholar: lookup
  41. Paillot R., Daly J.M., Juillard V., Minke J.M., Hannant D., Kydd J.H.. Equine Interferon Gamma Synthesis in Lymphocytes after in Vivo Infection and in Vitro Stimulation with EHV-1. Vaccine 2005;23:4541–4551.
    doi: 10.1016/j.vaccine.2005.03.048pubmed: 15913852google scholar: lookup
  42. Wagner B., Goodman L.B., Babasyan S., Freer H., Torsteinsdóttir S., Svansson V., Björnsdóttir S., Perkins G.A.. Antibody and Cellular Immune Responses of Naïve Mares to Repeated Vaccination with an Inactivated Equine Herpesvirus Vaccine. Vaccine 2015;33:5588–5597.
    doi: 10.1016/j.vaccine.2015.09.009pubmed: 26384446google scholar: lookup
  43. Breathnach C.C., Soboll G., Suresh M., Lunn D.P.. Equine Herpesvirus-1 Infection Induces IFN-γ Production by Equine T Lymphocyte Subsets. Vet. Immunol. Immunopathol. 2005;103:207–215.
    doi: 10.1016/j.vetimm.2004.09.024pubmed: 15621307google scholar: lookup
  44. Goodman L.B., Wimer C., Dubovi E.J., Gold C., Wagner B.. Immunological Correlates of Vaccination and Infection for Equine Herpesvirus 1. Clin. Vaccine Immunol. 2012;19:235–241.
    doi: 10.1128/CVI.05522-11pmc: PMC3272919pubmed: 22205656google scholar: lookup
  45. Wagner B., Perkins G., Babasyan S., Freer H., Keggan A., Goodman L.B., Glaser A., Torsteinsdóttir S., Svansson V., Björnsdóttir S.. Neonatal Immunization with a Single IL-4/Antigen Dose Induces Increased Antibody Responses after Challenge Infection with Equine Herpesvirus Type 1 (EHV-1) at Weanling Age. PLoS ONE 2017;12:e0169072.
  46. Alber D.G., Greensill J., Killington R.A., Stokes A.. Role of T-Cells, Virus Neutralising Antibodies and Complement-Mediated Antibody Lysis in the Immune Response against Equine Herpesvirus Type-1 (EHV-1) Infection of C3H (H-2k) and BALE/c (H-2d) Mice. Res. Vet. Sci. 1995;59:205–213.
    doi: 10.1016/0034-5288(95)90003-9pubmed: 8588092google scholar: lookup
  47. Azmi M., Field H.J.. Interactions between Equine Herpesvirus Type 1 and Equine Herpesvirus Type 4: T Cell Responses in a Murine Infection Model. J. Gen. Virol. 1993;74:2339–2345.
    doi: 10.1099/0022-1317-74-11-2339pubmed: 8245851google scholar: lookup
  48. Zhang C.H., Davis W.C., Grünig G., Antczak D.F.. The Equine Homologue of LFA-1 (CD11a/CD18): Cellular Distribution and Differential Determinants. Vet. Immunol. Immunopathol. 1998;62:167–183.
    doi: 10.1016/S0165-2427(97)00163-3pubmed: 9638860google scholar: lookup
  49. Kydd J., Antczak D.F., Allen W.R., Barbis D., Butcher G., Davis W., Duffus W.P.H., Edington N., Grünig G., Holmes M.A.. Report of the First International Workshop on Equine Leucocyte Antigens, Cambridge, UK, July 1991. Vet. Immunol. Immunopathol. 1994;42:3–60.
    doi: 10.1016/0165-2427(94)90088-4pubmed: 7975180google scholar: lookup
  50. Lunn D.P., Holmes M.A., Antczak D.F., Agerwal N., Baker J., Bendali-Ahcene S., Blanchard-Channell M., Byrne K.M., Cannizzo K., Davis W.. Report of the Second Equine Leucocyte Antigen Workshop, Squaw Valley, California, July 1995. Vet. Immunol. Immunopathol. 1998;62:101–143.
    doi: 10.1016/S0165-2427(97)00160-8pubmed: 9638857google scholar: lookup
  51. Wagner B., Babasyan S., Wilford S., Robbin M.G., De Mestre A.M.. Monoclonal Antibodies for Equine CD25 Improve Detection of Regulatory T Cells in Horses. Vet. Immunol. Immunopathol. 2024;274:110790.
    doi: 10.1016/j.vetimm.2024.110790pubmed: 38901326google scholar: lookup
  52. Noronha L.E., Harman R.M., Wagner B., Antczak D.F.. Generation and Characterization of Monoclonal Antibodies to Equine NKp46. Vet. Immunol. Immunopathol. 2012;147:60–68.
  53. Wagner B., Glaser A., Hillegas J.M., Erb H., Gold C., Freer H.. Monoclonal Antibodies to Equine IgM Improve the Sensitivity of West Nile Virus-Specific IgM Detection in Horses. Vet. Immunol. Immunopathol. 2008;122:46–56.
    doi: 10.1016/j.vetimm.2007.10.013pubmed: 18054390google scholar: lookup
  54. Kabithe E., Hillegas J., Stokol T., Moore J., Wagner B.. Monoclonal Antibodies to Equine CD14. Vet. Immunol. Immunopathol. 2010;138:149–153.
    doi: 10.1016/j.vetimm.2010.07.003pubmed: 20674042google scholar: lookup
  55. Wagner B., Freer H.. Development of a Bead-Based Multiplex Assay for Simultaneous Quantification of Cytokines in Horses. Vet. Immunol. Immunopathol. 2009;127:242–248.
    doi: 10.1016/j.vetimm.2008.10.313pubmed: 19027964google scholar: lookup
  56. Mair T.S., Batten E.H., Stokes C.R., Bourne F.J.. The Histological Features of the Immune System of the Equine Respiratory Tract. J. Comp. Pathol. 1987;97:575–586.
    doi: 10.1016/0021-9975(87)90008-9pubmed: 3680645google scholar: lookup
  57. Kumar P., Timoney J.F.. Light and Electron Microscope Studies on the Nasopharynx and Nasopharyngeal Tonsil of the Horse. Anat. Histol. Embryol. 2001;30:77–84.
  58. Kumar P., Timoney J.F., Sheoran A.S.. M Cells and Associated Lymphoid Tissue of the Equine Nasopharyngeal Tonsil. Equine Vet. J. 2001;33:224–230.
    doi: 10.2746/042516401776249697pubmed: 11352342google scholar: lookup
  59. Turner D.L., Bickham K.L., Thome J.J., Kim C.Y., D’Ovidio F., Wherry E.J., Farber D.L.. Lung Niches for the Generation and Maintenance of Tissue-Resident Memory T Cells. Mucosal Immunol. 2014;7:501–510.
    doi: 10.1038/mi.2013.67pmc: PMC3965651pubmed: 24064670google scholar: lookup
  60. Teijaro J.R., Turner D., Pham Q., Wherry E.J., Lefrançois L., Farber D.L.. Cutting Edge: Tissue-Retentive Lung Memory CD4 T Cells Mediate Optimal Protection to Respiratory Virus Infection. J. Immunol. 2011;187:5510–5514.
    doi: 10.4049/jimmunol.1102243pmc: PMC3221837pubmed: 22058417google scholar: lookup
  61. Jozwik A., Habibi M.S., Paras A., Zhu J., Guvenel A., Dhariwal J., Almond M., Wong E.H.C., Sykes A., Maybeno M.. RSV-Specific Airway Resident Memory CD8+ T Cells and Differential Disease Severity after Experimental Human Infection. Nat. Commun. 2015;6:10224.
    doi: 10.1038/ncomms10224pmc: PMC4703893pubmed: 26687547google scholar: lookup
  62. Vukmanovic-Stejic M., Sandhu D., Seidel J.A., Patel N., Sobande T.O., Agius E., Jackson S.E., Fuentes-Duculan J., Suárez-Fariñas M., Mabbott N.A.. The Characterization of Varicella Zoster Virus–Specific T Cells in Skin and Blood during Aging. J. Investig. Dermatol. 2015;135:1752–1762.
    doi: 10.1038/jid.2015.63pmc: PMC4471118pubmed: 25734814google scholar: lookup
  63. Posavad C.M., Remington M., Mueller D.E., Zhao L., Magaret A.S., Wald A., Corey L.. Detailed Characterization of T Cell Responses to Herpes Simplex Virus-2 in Immune Seronegative Persons. J. Immunol. 2010;184:3250–3259.
    doi: 10.4049/jimmunol.0900722pmc: PMC2877513pubmed: 20164419google scholar: lookup
  64. Traxinger B.R., Richert-Spuhler L.E., Lund J.M.. Mucosal Tissue Regulatory T Cells Are Integral in Balancing Immunity and Tolerance at Portals of Antigen Entry. Mucosal Immunol. 2022;15:398–407.
    doi: 10.1038/s41385-021-00471-xpmc: PMC8628059pubmed: 34845322google scholar: lookup
  65. Edmans M.D., Connelley T.K., Morgan S., Pediongco T.J., Jayaraman S., Juno J.A., Meehan B.S., Dewar P.M., Maze E.A., Roos E.O.. MAIT Cell-MR1 Reactivity Is Highly Conserved across Multiple Divergent Species. J. Biol. Chem. 2024;300:107338.
    doi: 10.1016/j.jbc.2024.107338pmc: PMC11190491pubmed: 38705391google scholar: lookup
  66. Mayassi T., Barreiro L.B., Rossjohn J., Jabri B.. A Multilayered Immune System through the Lens of Unconventional T Cells. Nature 2021;595:501–510.
    doi: 10.1038/s41586-021-03578-0pmc: PMC8514118pubmed: 34290426google scholar: lookup
  67. Nel I., Bertrand L., Toubal A., Lehuen A.. MAIT Cells, Guardians of Skin and Mucosa?. Mucosal Immunol. 2021;14:803–814.
    doi: 10.1038/s41385-021-00391-wpmc: PMC7983967pubmed: 33753874google scholar: lookup
  68. Vandereyken M., James O.J., Swamy M.. Mechanisms of Activation of Innate-like Intraepithelial T Lymphocytes. Mucosal Immunol. 2020;13:721–731.
    doi: 10.1038/s41385-020-0294-6pmc: PMC7434593pubmed: 32415229google scholar: lookup
  69. Koay H.-F., Gherardin N.A., Enders A., Loh L., Mackay L.K., Almeida C.F., Russ B.E., Nold-Petry C.A., Nold M.F., Bedoui S.. A Three-Stage Intrathymic Development Pathway for the Mucosal-Associated Invariant T Cell Lineage. Nat. Immunol. 2016;17:1300–1311.
    doi: 10.1038/ni.3565pubmed: 27668799google scholar: lookup
  70. Kumar B.V., Ma W., Miron M., Granot T., Guyer R.S., Carpenter D.J., Senda T., Sun X., Ho S.-H., Lerner H.. Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites. Cell Rep. 2017;20:2921–2934.
  71. Hu Y., Hu Q., Li Y., Lu L., Xiang Z., Yin Z., Kabelitz D., Wu Y.. Γδ T Cells: Origin and Fate, Subsets, Diseases and Immunotherapy. Sig Transduct. Target. Ther. 2023;8:1–38.
    doi: 10.1038/s41392-023-01653-8pmc: PMC10663641pubmed: 37989744google scholar: lookup
  72. Mucida D., Husain M.M., Muroi S., Van Wijk F., Shinnakasu R., Naoe Y., Reis B.S., Huang Y., Lambolez F., Docherty M.. Transcriptional Reprogramming of Mature CD4+ Helper T Cells Generates Distinct MHC Class II–Restricted Cytotoxic T Lymphocytes. Nat. Immunol. 2013;14:281–289.
    doi: 10.1038/ni.2523pmc: PMC3581083pubmed: 23334788google scholar: lookup
  73. Wang L., Wildt K.F., Castro E., Xiong Y., Feigenbaum L., Tessarollo L., Bosselut R.. The Zinc Finger Transcription Factor Zbtb7b Represses CD8-Lineage Gene Expression in Peripheral CD4+ T Cells. Immunity 2008;29:876–887.
  74. Setoguchi R., Tachibana M., Naoe Y., Muroi S., Akiyama K., Tezuka C., Okuda T., Taniuchi I.. Repression of the Transcription Factor Th-POK by Runx Complexes in Cytotoxic T Cell Development. Science 2008;319:822–825.
    doi: 10.1126/science.1151844pubmed: 18258917google scholar: lookup
  75. Reis B.S., Rogoz A., Costa-Pinto F.A., Taniuchi I., Mucida D.. Mutual Expression of the Transcription Factors Runx3 and ThPOK Regulates Intestinal CD4+ T Cell Immunity. Nat. Immunol. 2013;14:271–280.
    doi: 10.1038/ni.2518pmc: PMC3804366pubmed: 23334789google scholar: lookup
  76. Van Kaer L., Rabacal W.A.S., Scott Algood H.M., Parekh V.V., Olivares-Villagómez D.. In Vitro Induction of Regulatory CD4+CD8α+ T Cells by TGF-β, IL-7 and IFN-γ. PLoS ONE 2013;8:e67821.
  77. Sullivan Y.B., Landay A.L., Zack J.A., Kitchen S.G., Al-Harthi L.. Upregulation of CD4 on CD8 + T Cells: CD4 dim CD8 bright T Cells Constitute an Activated Phenotype of CD8 + T Cells. Immunology 2001;103:270–280.
  78. Zuckermann F.A.. Extrathymic CD4/CD8 Double Positive T Cells. Vet. Immunol. Immunopathol. 1999;72:55–66.
    doi: 10.1016/S0165-2427(99)00118-Xpubmed: 10614493google scholar: lookup
  79. Abuzakouk M., Carton J., Feighery C., O’Donoghue D.P., Weir D.G., O’Farrelly C.. CD4+CD8+ and CD8α+β- T Lymphocytes in Human Small Intestinal Lamina Propria. Eur. J. Gastroenterol. Hepatol. 1998;10:325–330.
  80. Solano-Aguilar G.I., Vengroski K.G., Beshah E., Douglass L.W., Lunney J.K.. Characterization of Lymphocyte Subsets from Mucosal Tissues in Neonatal Swine. Dev. Comp. Immunol. 2001;25:245–263.
    doi: 10.1016/S0145-305X(00)00053-7pubmed: 11164889google scholar: lookup
  81. Kitchen S.G., Jones N.R., LaForge S., Whitmire J.K., Vu B.-A., Galic Z., Brooks D.G., Brown S.J., Kitchen C.M.R., Zack J.A.. CD4 on CD8 + T Cells Directly Enhances Effector Function and Is a Target for HIV Infection. Proc. Natl. Acad. Sci. USA 2004;101:8727–8732.
    doi: 10.1073/pnas.0401500101pmc: PMC423263pubmed: 15173593google scholar: lookup
  82. Kydd J.H., Hannant D., Mumford J.A.. Residence and Recruitment of Leucocytes to the Equine Lung after EHV-1 Infection. Vet. Immunol. Immunopathol. 1996;52:15–26.
    doi: 10.1016/0165-2427(95)05533-9pubmed: 8807773google scholar: lookup
  83. Pizzolla A., Nguyen T.H.O., Smith J.M., Brooks A.G., Kedzierska K., Heath W.R., Reading P.C., Wakim L.M.. Resident Memory CD8+ T Cells in the Upper Respiratory Tract Prevent Pulmonary Influenza Virus Infection. Sci. Immunol. 2017;2:eaam6970.
    doi: 10.1126/sciimmunol.aam6970pubmed: 28783656google scholar: lookup
  84. Negussie H., Li Y., Tessema T.S., Nauwynck H.J.. Replication Characteristics of Equine Herpesvirus 1 and Equine Herpesvirus 3: Comparative Analysis Using Ex Vivo Tissue Cultures. Vet. Res. 2016;47:19.
    doi: 10.1186/s13567-016-0305-5pmc: PMC4714513pubmed: 26768993google scholar: lookup