Imprinting of Gut-Homing Receptors on Mtb-Specific Th1* Cells Is Associated with Reduced Lung Homing after Gavage BCG Vaccination of Rhesus Macaques
ABSTRACT Alternative delivery routes of the current Mycobacterium tuberculosis (Mtb) vaccine, intradermally (ID) delivered BCG, may provide better protection against tuberculosis, and be more easily administered. Here, we use rhesus macaques to compare the airway immunogenicity of BCG delivered via...
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| Format: | Article |
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American Society for Microbiology
2023-04-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00220-23 |
| _version_ | 1797839582877712384 |
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| author | Stella G. Hoft Keith D. Kauffman Shunsuke Sakai Cecilia S. Lindestam Arlehamn Alessandro Sette Daniel F. Hoft Richard Herbert Daniel L. Barber |
| author_facet | Stella G. Hoft Keith D. Kauffman Shunsuke Sakai Cecilia S. Lindestam Arlehamn Alessandro Sette Daniel F. Hoft Richard Herbert Daniel L. Barber |
| author_sort | Stella G. Hoft |
| collection | DOAJ |
| description | ABSTRACT Alternative delivery routes of the current Mycobacterium tuberculosis (Mtb) vaccine, intradermally (ID) delivered BCG, may provide better protection against tuberculosis, and be more easily administered. Here, we use rhesus macaques to compare the airway immunogenicity of BCG delivered via either ID or intragastric gavage vaccination. Ag-specific CD4 T cell responses in the blood were similar after BCG vaccination via gavage or ID injection. However, gavage BCG vaccination induced significantly lower T cell responses in the airways compared to intradermal BCG vaccination. Examining T cell responses in lymph node biopsies showed that ID vaccination induced T cell priming in skin-draining lymph nodes, while gavage vaccination induced priming in the gut-draining nodes, as expected. While both delivery routes induced highly functional Ag-specific CD4 T cells with a Th1* phenotype (CXCR3+CCR6+), gavage vaccination induced the co-expression of the gut-homing integrin α4β7 on Ag-specific Th1* cells, which was associated with reduced migration into the airways. Thus, in rhesus macaques, the airway immunogenicity of gavage BCG vaccination may be limited by the imprinting of gut-homing receptors on Ag-specific T cells primed in intestinal lymph nodes. IMPORTANCE Mycobacterium tuberculosis (Mtb) is a leading cause of global infectious disease mortality. The vaccine for Mtb, Bacillus Calmette-Guérin (BCG), was originally developed as an oral vaccine, but is now given intradermally. Recently, clinical studies have reevaluated oral BCG vaccination in humans and found that it induces significant T cell responses in the airways. Here, we use rhesus macaques to compare the airway immunogenicity of BCG delivered intradermally or via intragastric gavage. We find that gavage BCG vaccination induces Mtb-specific T cell responses in the airways, but to a lesser extent than intradermal vaccination. Furthermore, gavage BCG vaccination induces the gut-homing receptor a4ß7 on Mtb-specific CD4 T cells, which was associated with reduced migration into the airways. These data raise the possibility that strategies to limit the induction of gut-homing receptors on responding T cells may enhance the airway immunogenicity of oral vaccines. |
| first_indexed | 2024-04-09T16:00:17Z |
| format | Article |
| id | doaj.art-0ede394fe9264bd2be150bdaf50800d8 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-09T16:00:17Z |
| publishDate | 2023-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-0ede394fe9264bd2be150bdaf50800d82023-04-25T13:04:57ZengAmerican Society for MicrobiologymBio2150-75112023-04-0114210.1128/mbio.00220-23Imprinting of Gut-Homing Receptors on Mtb-Specific Th1* Cells Is Associated with Reduced Lung Homing after Gavage BCG Vaccination of Rhesus MacaquesStella G. Hoft0Keith D. Kauffman1Shunsuke Sakai2Cecilia S. Lindestam Arlehamn3Alessandro Sette4Daniel F. Hoft5Richard Herbert6Daniel L. Barber7T lymphocyte Biology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USAT lymphocyte Biology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USAT lymphocyte Biology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USACenter for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, California, USACenter for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, California, USADivision of Infectious Diseases, Allergy, and Immunology, Department of Internal Medicine, Department of Molecular Microbiology & Immunology, Saint Louis University, Saint Louis, Missouri, USAExperimental Primate Virology Section, Comparative Medicine Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Poolesville, Maryland, USAT lymphocyte Biology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USAABSTRACT Alternative delivery routes of the current Mycobacterium tuberculosis (Mtb) vaccine, intradermally (ID) delivered BCG, may provide better protection against tuberculosis, and be more easily administered. Here, we use rhesus macaques to compare the airway immunogenicity of BCG delivered via either ID or intragastric gavage vaccination. Ag-specific CD4 T cell responses in the blood were similar after BCG vaccination via gavage or ID injection. However, gavage BCG vaccination induced significantly lower T cell responses in the airways compared to intradermal BCG vaccination. Examining T cell responses in lymph node biopsies showed that ID vaccination induced T cell priming in skin-draining lymph nodes, while gavage vaccination induced priming in the gut-draining nodes, as expected. While both delivery routes induced highly functional Ag-specific CD4 T cells with a Th1* phenotype (CXCR3+CCR6+), gavage vaccination induced the co-expression of the gut-homing integrin α4β7 on Ag-specific Th1* cells, which was associated with reduced migration into the airways. Thus, in rhesus macaques, the airway immunogenicity of gavage BCG vaccination may be limited by the imprinting of gut-homing receptors on Ag-specific T cells primed in intestinal lymph nodes. IMPORTANCE Mycobacterium tuberculosis (Mtb) is a leading cause of global infectious disease mortality. The vaccine for Mtb, Bacillus Calmette-Guérin (BCG), was originally developed as an oral vaccine, but is now given intradermally. Recently, clinical studies have reevaluated oral BCG vaccination in humans and found that it induces significant T cell responses in the airways. Here, we use rhesus macaques to compare the airway immunogenicity of BCG delivered intradermally or via intragastric gavage. We find that gavage BCG vaccination induces Mtb-specific T cell responses in the airways, but to a lesser extent than intradermal vaccination. Furthermore, gavage BCG vaccination induces the gut-homing receptor a4ß7 on Mtb-specific CD4 T cells, which was associated with reduced migration into the airways. These data raise the possibility that strategies to limit the induction of gut-homing receptors on responding T cells may enhance the airway immunogenicity of oral vaccines.https://journals.asm.org/doi/10.1128/mbio.00220-23BCGCD4 T cellsimmunizationimmunologylung defenserhesus macaques |
| spellingShingle | Stella G. Hoft Keith D. Kauffman Shunsuke Sakai Cecilia S. Lindestam Arlehamn Alessandro Sette Daniel F. Hoft Richard Herbert Daniel L. Barber Imprinting of Gut-Homing Receptors on Mtb-Specific Th1* Cells Is Associated with Reduced Lung Homing after Gavage BCG Vaccination of Rhesus Macaques mBio BCG CD4 T cells immunization immunology lung defense rhesus macaques |
| title | Imprinting of Gut-Homing Receptors on Mtb-Specific Th1* Cells Is Associated with Reduced Lung Homing after Gavage BCG Vaccination of Rhesus Macaques |
| title_full | Imprinting of Gut-Homing Receptors on Mtb-Specific Th1* Cells Is Associated with Reduced Lung Homing after Gavage BCG Vaccination of Rhesus Macaques |
| title_fullStr | Imprinting of Gut-Homing Receptors on Mtb-Specific Th1* Cells Is Associated with Reduced Lung Homing after Gavage BCG Vaccination of Rhesus Macaques |
| title_full_unstemmed | Imprinting of Gut-Homing Receptors on Mtb-Specific Th1* Cells Is Associated with Reduced Lung Homing after Gavage BCG Vaccination of Rhesus Macaques |
| title_short | Imprinting of Gut-Homing Receptors on Mtb-Specific Th1* Cells Is Associated with Reduced Lung Homing after Gavage BCG Vaccination of Rhesus Macaques |
| title_sort | imprinting of gut homing receptors on mtb specific th1 cells is associated with reduced lung homing after gavage bcg vaccination of rhesus macaques |
| topic | BCG CD4 T cells immunization immunology lung defense rhesus macaques |
| url | https://journals.asm.org/doi/10.1128/mbio.00220-23 |
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