Abstract
Immune responses at mucosal sites are thought to be initiated in the draining lymph nodes, where dendritic cells present viral antigens and induce naive T cells to proliferate and to become effectors. Formal proof that antigen-presenting cells (APC) do indeed localize to the regional lymph nodes has been lacking for viral infections of the respiratory tract. Influenza virus was detected in the draining mediastinal lymph nodes (MLN) early after intranasal inoculation, with peak virus titers in this tissue measured at 2 days postinfection. Virus-specific cytotoxic T-lymphocyte responses were first detected in the MLN 1 day later. Macrophages, dendritic cells, and B lymphocytes were isolated from influenza virus-infected mice and assayed for the capacity to stimulate a major histocompatibility complex class I-restricted virus-specific T-cell hybridoma. All APC populations from lungs and MLN contained virus and thus had the potential to present antigen to CD8+ T cells. The APC recovered from the lungs of influenza virus-infected mice and dendritic cells from the MLN were able to stimulate virus-specific responses. The lack of a virus-specific T-cell response to B cells corresponds to the small number of virus-positive B lymphocytes in the MLN. These results indicate that dendritic cells and macrophages are antigen positive in mice acutely infected with an influenza A virus and that dendritic cells are probably responsible for initiating the cytotoxic T-lymphocyte response to influenza virus in the draining lymph nodes.
Full Text
The Full Text of this article is available as a PDF (332.4 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Allan W., Tabi Z., Cleary A., Doherty P. C. Cellular events in the lymph node and lung of mice with influenza. Consequences of depleting CD4+ T cells. J Immunol. 1990 May 15;144(10):3980–3986. [PubMed] [Google Scholar]
- Cassell D. J., Schwartz R. H. A quantitative analysis of antigen-presenting cell function: activated B cells stimulate naive CD4 T cells but are inferior to dendritic cells in providing costimulation. J Exp Med. 1994 Nov 1;180(5):1829–1840. doi: 10.1084/jem.180.5.1829. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Coffman R. L. Surface antigen expression and immunoglobulin gene rearrangement during mouse pre-B cell development. Immunol Rev. 1982;69:5–23. doi: 10.1111/j.1600-065x.1983.tb00446.x. [DOI] [PubMed] [Google Scholar]
- Cole G. A., Hogg T. L., Woodland D. L. The MHC class I-restricted T cell response to Sendai virus infection in C57BL/6 mice: a single immunodominant epitope elicits an extremely diverse repertoire of T cells. Int Immunol. 1994 Nov;6(11):1767–1775. doi: 10.1093/intimm/6.11.1767. [DOI] [PubMed] [Google Scholar]
- Deckhut A. M., Allan W., McMickle A., Eichelberger M., Blackman M. A., Doherty P. C., Woodland D. L. Prominent usage of V beta 8.3 T cells in the H-2Db-restricted response to an influenza A virus nucleoprotein epitope. J Immunol. 1993 Sep 1;151(5):2658–2666. [PubMed] [Google Scholar]
- Doherty P. C., Allan W., Eichelberger M., Carding S. R. Roles of alpha beta and gamma delta T cell subsets in viral immunity. Annu Rev Immunol. 1992;10:123–151. doi: 10.1146/annurev.iy.10.040192.001011. [DOI] [PubMed] [Google Scholar]
- Eichelberger M. C., Wang M. L., Allan W., Webster R. G., Doherty P. C. Influenza virus RNA in the lung and lymphoid tissue of immunologically intact and CD4-depleted mice. J Gen Virol. 1991 Jul;72(Pt 7):1695–1698. doi: 10.1099/0022-1317-72-7-1695. [DOI] [PubMed] [Google Scholar]
- Eichelberger M., Allan W., Zijlstra M., Jaenisch R., Doherty P. C. Clearance of influenza virus respiratory infection in mice lacking class I major histocompatibility complex-restricted CD8+ T cells. J Exp Med. 1991 Oct 1;174(4):875–880. doi: 10.1084/jem.174.4.875. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fazekas de St Groth, Webster R. G. Disquisitions of Original Antigenic Sin. I. Evidence in man. J Exp Med. 1966 Sep 1;124(3):331–345. doi: 10.1084/jem.124.3.331. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fuchs E. J., Matzinger P. B cells turn off virgin but not memory T cells. Science. 1992 Nov 13;258(5085):1156–1159. doi: 10.1126/science.1439825. [DOI] [PubMed] [Google Scholar]
- Gillis S., Smith K. A. Long term culture of tumour-specific cytotoxic T cells. Nature. 1977 Jul 14;268(5616):154–156. doi: 10.1038/268154a0. [DOI] [PubMed] [Google Scholar]
- Holt P. G., Oliver J., Bilyk N., McMenamin C., McMenamin P. G., Kraal G., Thepen T. Downregulation of the antigen presenting cell function(s) of pulmonary dendritic cells in vivo by resident alveolar macrophages. J Exp Med. 1993 Feb 1;177(2):397–407. doi: 10.1084/jem.177.2.397. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kappler J. W., Skidmore B., White J., Marrack P. Antigen-inducible, H-2-restricted, interleukin-2-producing T cell hybridomas. Lack of independent antigen and H-2 recognition. J Exp Med. 1981 May 1;153(5):1198–1214. doi: 10.1084/jem.153.5.1198. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kilbourne E. D. Future influenza vaccines and the use of genetic recombinants. Bull World Health Organ. 1969;41(3):643–645. [PMC free article] [PubMed] [Google Scholar]
- Kubo R. T., Born W., Kappler J. W., Marrack P., Pigeon M. Characterization of a monoclonal antibody which detects all murine alpha beta T cell receptors. J Immunol. 1989 Apr 15;142(8):2736–2742. [PubMed] [Google Scholar]
- Larsen C. P., Ritchie S. C., Hendrix R., Linsley P. S., Hathcock K. S., Hodes R. J., Lowry R. P., Pearson T. C. Regulation of immunostimulatory function and costimulatory molecule (B7-1 and B7-2) expression on murine dendritic cells. J Immunol. 1994 Jun 1;152(11):5208–5219. [PubMed] [Google Scholar]
- Ledbetter J. A., Herzenberg L. A. Xenogeneic monoclonal antibodies to mouse lymphoid differentiation antigens. Immunol Rev. 1979;47:63–90. doi: 10.1111/j.1600-065x.1979.tb00289.x. [DOI] [PubMed] [Google Scholar]
- Liu T., Zhou X., Orvell C., Lederer E., Ljunggren H. G., Jondal M. Heat-inactivated Sendai virus can enter multiple MHC class I processing pathways and generate cytotoxic T lymphocyte responses in vivo. J Immunol. 1995 Apr 1;154(7):3147–3155. [PubMed] [Google Scholar]
- London S. D., Rubin D. H., Cebra J. J. Gut mucosal immunization with reovirus serotype 1/L stimulates virus-specific cytotoxic T cell precursors as well as IgA memory cells in Peyer's patches. J Exp Med. 1987 Mar 1;165(3):830–847. doi: 10.1084/jem.165.3.830. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Macatonia S. E., Taylor P. M., Knight S. C., Askonas B. A. Primary stimulation by dendritic cells induces antiviral proliferative and cytotoxic T cell responses in vitro. J Exp Med. 1989 Apr 1;169(4):1255–1264. doi: 10.1084/jem.169.4.1255. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McMichael A. J., Gotch F. M., Noble G. R., Beare P. A. Cytotoxic T-cell immunity to influenza. N Engl J Med. 1983 Jul 7;309(1):13–17. doi: 10.1056/NEJM198307073090103. [DOI] [PubMed] [Google Scholar]
- McWilliam A. S., Nelson D., Thomas J. A., Holt P. G. Rapid dendritic cell recruitment is a hallmark of the acute inflammatory response at mucosal surfaces. J Exp Med. 1994 Apr 1;179(4):1331–1336. doi: 10.1084/jem.179.4.1331. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Metlay J. P., Puré E., Steinman R. M. Control of the immune response at the level of antigen-presenting cells: a comparison of the function of dendritic cells and B lymphocytes. Adv Immunol. 1989;47:45–116. doi: 10.1016/s0065-2776(08)60662-8. [DOI] [PubMed] [Google Scholar]
- Metlay J. P., Witmer-Pack M. D., Agger R., Crowley M. T., Lawless D., Steinman R. M. The distinct leukocyte integrins of mouse spleen dendritic cells as identified with new hamster monoclonal antibodies. J Exp Med. 1990 May 1;171(5):1753–1771. doi: 10.1084/jem.171.5.1753. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Morris S. C., Lees A., Finkelman F. D. In vivo activation of naive T cells by antigen-presenting B cells. J Immunol. 1994 Apr 15;152(8):3777–3785. [PubMed] [Google Scholar]
- Pollard A. M., Lipscomb M. F. Characterization of murine lung dendritic cells: similarities to Langerhans cells and thymic dendritic cells. J Exp Med. 1990 Jul 1;172(1):159–167. doi: 10.1084/jem.172.1.159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ronchese F., Hausmann B. B lymphocytes in vivo fail to prime naive T cells but can stimulate antigen-experienced T lymphocytes. J Exp Med. 1993 Mar 1;177(3):679–690. doi: 10.1084/jem.177.3.679. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schon-Hegrad M. A., Oliver J., McMenamin P. G., Holt P. G. Studies on the density, distribution, and surface phenotype of intraepithelial class II major histocompatibility complex antigen (Ia)-bearing dendritic cells (DC) in the conducting airways. J Exp Med. 1991 Jun 1;173(6):1345–1356. doi: 10.1084/jem.173.6.1345. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sklar M. D., Tereba A., Chen B. D., Walker W. S. Transformation of mouse bone marrow cells by transfection with a human oncogene related to c-myc is associated with the endogenous production of macrophage colony stimulating factor 1. J Cell Physiol. 1985 Dec;125(3):403–412. doi: 10.1002/jcp.1041250307. [DOI] [PubMed] [Google Scholar]
- Springer T., Galfré G., Secher D. S., Milstein C. Mac-1: a macrophage differentiation antigen identified by monoclonal antibody. Eur J Immunol. 1979 Apr;9(4):301–306. doi: 10.1002/eji.1830090410. [DOI] [PubMed] [Google Scholar]
- Steinman R. M. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271–296. doi: 10.1146/annurev.iy.09.040191.001415. [DOI] [PubMed] [Google Scholar]
- Steinman R. M., Witmer M. D. Lymphoid dendritic cells are potent stimulators of the primary mixed leukocyte reaction in mice. Proc Natl Acad Sci U S A. 1978 Oct;75(10):5132–5136. doi: 10.1073/pnas.75.10.5132. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tabi Z., Lynch F., Ceredig R., Allan J. E., Doherty P. C. Virus-specific memory T cells are Pgp-1+ and can be selectively activated with phorbol ester and calcium ionophore. Cell Immunol. 1988 May;113(2):268–277. doi: 10.1016/0008-8749(88)90026-3. [DOI] [PubMed] [Google Scholar]
- Townsend A. R., Rothbard J., Gotch F. M., Bahadur G., Wraith D., McMichael A. J. The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell. 1986 Mar 28;44(6):959–968. doi: 10.1016/0092-8674(86)90019-x. [DOI] [PubMed] [Google Scholar]
- Wells M. A., Albrecht P., Daniel S., Ennis F. A. Host defense mechanisms against influenza virus: interaction of influenza virus with murine macrophages in vitro. Infect Immun. 1978 Dec;22(3):758–762. doi: 10.1128/iai.22.3.758-762.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wilson C. M., Gatewood J. W., McCormack J. M., Walker W. S. Immortalization of growth factor-dependent mouse splenic macrophages derived from cloned progenitors. J Immunol Methods. 1991 Mar 1;137(1):17–25. doi: 10.1016/0022-1759(91)90389-w. [DOI] [PubMed] [Google Scholar]
