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Bone marrow-derived antigen-presenting cells are required for the generation of cytotoxic T lymphocyte responses to viruses and use transporter associated with antigen presentation (TAP)-dependent and -independent pathways of antigen presentation.

Sigal LJ, Rock KL - J. Exp. Med. (2000)

Bottom Line: Furthermore, these BM-derived pAPCs require a functional transporter associated with antigen presentation (TAP).However, we found that the generation of CTLs to one LCMV epitope (LCMV nucleoprotein 396-404) was dependent on BM-derived pAPCs but, surprisingly, TAP independent.The study of the CTL response to Flu confirmed the existence of this BM-derived pAPC-dependent/TAP-independent CTL response and indicated that the TAP-independent pathway is approximately 10-300-fold less efficient than the TAP-dependent pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655, USA. lj_sigal@fccc.edu

ABSTRACT
Bone marrow (BM)-derived professional antigen-presenting cells (pAPCs) are required for the generation of cytotoxic T lymphocyte (CTL) responses to vaccinia virus and poliovirus. Furthermore, these BM-derived pAPCs require a functional transporter associated with antigen presentation (TAP). In this report we analyze the requirements for BM-derived pAPCs and TAP in the initiation of CTL responses to lymphocytic choriomeningitis virus (LCMV) and influenza virus (Flu). Our results indicate a requirement for BM-derived pAPCs for the CTL responses to these viruses. However, we found that the generation of CTLs to one LCMV epitope (LCMV nucleoprotein 396-404) was dependent on BM-derived pAPCs but, surprisingly, TAP independent. The study of the CTL response to Flu confirmed the existence of this BM-derived pAPC-dependent/TAP-independent CTL response and indicated that the TAP-independent pathway is approximately 10-300-fold less efficient than the TAP-dependent pathway.

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The CTL response to Flu np147–155 in B6→B6D2 is abrogated by supralethally irradiating recipient mice. Supralethally irradiated chimeras of the type B6→B6D2 (left panels; four animals) and B6D2→B6D2 (right panels; five animals) were infected with 73 HAU Flu A/PR8/34. CTL assays were performed with spleen cells that had been restimulated in vitro as described in Materials and Methods. Targets are as indicated. Each line corresponds to an individual mouse. Similar figures within a group of chimeras correspond to the same mouse (e.g., all squares in the B6→B6D2 group correspond to the same mouse recognizing different targets).
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Figure 6: The CTL response to Flu np147–155 in B6→B6D2 is abrogated by supralethally irradiating recipient mice. Supralethally irradiated chimeras of the type B6→B6D2 (left panels; four animals) and B6D2→B6D2 (right panels; five animals) were infected with 73 HAU Flu A/PR8/34. CTL assays were performed with spleen cells that had been restimulated in vitro as described in Materials and Methods. Targets are as indicated. Each line corresponds to an individual mouse. Similar figures within a group of chimeras correspond to the same mouse (e.g., all squares in the B6→B6D2 group correspond to the same mouse recognizing different targets).

Mentions: To determine the role of BM-derived pAPCs in the generation of CTLs to yet another virus, we decided to examine Flu for which the CTL response has been well characterized in the mouse 1. We inoculated B6→B6D2, D→B6D2, and B6D2→B6D2 mice with 73 HAU Flu. The results in the top panels of Fig. 5 clearly show that D2→B6D2 mice, which did not express the Db-restricting element on the BM-derived cells, did not generate CTLs to the Db-restricted epitope Flu np366–374, despite expression of Db on the recipient's nonhematopoietic cells. The lack of response was not due to the inability of D2→B6D2 mice to generate CTLs because they responded strongly to the Kd-restricted epitope Flu np147–155 (Fig. 5, bottom row, center panel). This clearly demonstrated the fundamental importance of BM-derived pAPCs in the generation of CTLs to Flu np366–374. The same groups of mice that were analyzed for the response to Flu np366–374 were also analyzed for the response to the Kd-restricted Flu np147–155 (Fig. 5, bottom panels). B6D2→B6D2 and D2→B6D2 mice generated strong responses to this epitope. This was expected because they expressed Kd in the vast majority of BM-derived cells, which were of donor origin. However, B6→B6D2 mice also generated CTL responses to Flu np147–155 despite the lack of expression of Kd in most BM-derived cells. To investigate whether this response was due to host- and BM-derived pAPCs that resisted irradiation, we generated supralethally irradiated chimeras (1,300 rads) of the types B6→B6D2 and B6D2→B6D2. The results in Fig. 6 show that supralethally irradiated B6→B6D2 mice did not respond to Flu np147–155 whereas B6D2→B6D2 mice did. This was not due to the inability of supralethally irradiated B6→B6D2 mice to mount CTL responses because they generated detectable responses to the Db-restricted Flu np366–374. These results demonstrate that BM-derived cells are required for the generation of CTLs to multiple epitopes of the Flu virus.


Bone marrow-derived antigen-presenting cells are required for the generation of cytotoxic T lymphocyte responses to viruses and use transporter associated with antigen presentation (TAP)-dependent and -independent pathways of antigen presentation.

Sigal LJ, Rock KL - J. Exp. Med. (2000)

The CTL response to Flu np147–155 in B6→B6D2 is abrogated by supralethally irradiating recipient mice. Supralethally irradiated chimeras of the type B6→B6D2 (left panels; four animals) and B6D2→B6D2 (right panels; five animals) were infected with 73 HAU Flu A/PR8/34. CTL assays were performed with spleen cells that had been restimulated in vitro as described in Materials and Methods. Targets are as indicated. Each line corresponds to an individual mouse. Similar figures within a group of chimeras correspond to the same mouse (e.g., all squares in the B6→B6D2 group correspond to the same mouse recognizing different targets).
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Related In: Results  -  Collection

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Figure 6: The CTL response to Flu np147–155 in B6→B6D2 is abrogated by supralethally irradiating recipient mice. Supralethally irradiated chimeras of the type B6→B6D2 (left panels; four animals) and B6D2→B6D2 (right panels; five animals) were infected with 73 HAU Flu A/PR8/34. CTL assays were performed with spleen cells that had been restimulated in vitro as described in Materials and Methods. Targets are as indicated. Each line corresponds to an individual mouse. Similar figures within a group of chimeras correspond to the same mouse (e.g., all squares in the B6→B6D2 group correspond to the same mouse recognizing different targets).
Mentions: To determine the role of BM-derived pAPCs in the generation of CTLs to yet another virus, we decided to examine Flu for which the CTL response has been well characterized in the mouse 1. We inoculated B6→B6D2, D→B6D2, and B6D2→B6D2 mice with 73 HAU Flu. The results in the top panels of Fig. 5 clearly show that D2→B6D2 mice, which did not express the Db-restricting element on the BM-derived cells, did not generate CTLs to the Db-restricted epitope Flu np366–374, despite expression of Db on the recipient's nonhematopoietic cells. The lack of response was not due to the inability of D2→B6D2 mice to generate CTLs because they responded strongly to the Kd-restricted epitope Flu np147–155 (Fig. 5, bottom row, center panel). This clearly demonstrated the fundamental importance of BM-derived pAPCs in the generation of CTLs to Flu np366–374. The same groups of mice that were analyzed for the response to Flu np366–374 were also analyzed for the response to the Kd-restricted Flu np147–155 (Fig. 5, bottom panels). B6D2→B6D2 and D2→B6D2 mice generated strong responses to this epitope. This was expected because they expressed Kd in the vast majority of BM-derived cells, which were of donor origin. However, B6→B6D2 mice also generated CTL responses to Flu np147–155 despite the lack of expression of Kd in most BM-derived cells. To investigate whether this response was due to host- and BM-derived pAPCs that resisted irradiation, we generated supralethally irradiated chimeras (1,300 rads) of the types B6→B6D2 and B6D2→B6D2. The results in Fig. 6 show that supralethally irradiated B6→B6D2 mice did not respond to Flu np147–155 whereas B6D2→B6D2 mice did. This was not due to the inability of supralethally irradiated B6→B6D2 mice to mount CTL responses because they generated detectable responses to the Db-restricted Flu np366–374. These results demonstrate that BM-derived cells are required for the generation of CTLs to multiple epitopes of the Flu virus.

Bottom Line: Furthermore, these BM-derived pAPCs require a functional transporter associated with antigen presentation (TAP).However, we found that the generation of CTLs to one LCMV epitope (LCMV nucleoprotein 396-404) was dependent on BM-derived pAPCs but, surprisingly, TAP independent.The study of the CTL response to Flu confirmed the existence of this BM-derived pAPC-dependent/TAP-independent CTL response and indicated that the TAP-independent pathway is approximately 10-300-fold less efficient than the TAP-dependent pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655, USA. lj_sigal@fccc.edu

ABSTRACT
Bone marrow (BM)-derived professional antigen-presenting cells (pAPCs) are required for the generation of cytotoxic T lymphocyte (CTL) responses to vaccinia virus and poliovirus. Furthermore, these BM-derived pAPCs require a functional transporter associated with antigen presentation (TAP). In this report we analyze the requirements for BM-derived pAPCs and TAP in the initiation of CTL responses to lymphocytic choriomeningitis virus (LCMV) and influenza virus (Flu). Our results indicate a requirement for BM-derived pAPCs for the CTL responses to these viruses. However, we found that the generation of CTLs to one LCMV epitope (LCMV nucleoprotein 396-404) was dependent on BM-derived pAPCs but, surprisingly, TAP independent. The study of the CTL response to Flu confirmed the existence of this BM-derived pAPC-dependent/TAP-independent CTL response and indicated that the TAP-independent pathway is approximately 10-300-fold less efficient than the TAP-dependent pathway.

Show MeSH
Related in: MedlinePlus