Mycobacteria‐reactive Lyt‐2<sup>+</sup> T cell lines

Libero, Gennaro De; Flesch, I; Kaufmann, Stefan H. E.

doi:10.1002/eji.1830180110

Cited by 171 publications

(91 citation statements)

References 49 publications

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“…Apart from the ability to make cytokines, CD8 ϩ T cells may also function as CTLs; the development of CD8 ϩ CTLs during acute murine tuberculosis has been documented (17,24,33,35,36,39). We demonstrated that, 3 weeks postchallenge, the lungs of memory mice contained CD8…”

Section: Cytotoxic Function Of Memory Cd8 ؉ T Cells Previously We Dmentioning

confidence: 84%

CD8⁺T Cells Participate in the Memory Immune Response toMycobacterium tuberculosis

2001

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The contribution of CD8؉ T cells to the control of tuberculosis has been studied primarily during acute infection in mouse models. Memory or recall responses in tuberculosis are less well characterized, particularly with respect to the CD8 T-cell subset. In fact, there are published reports that CD8 ؉ T cells do not participate in the memory immune response to Mycobacterium tuberculosis. We examined the CD8 ؉ T-cell memory and local recall response to M. tuberculosis. To establish a memory immunity model, C57BL/6 mice were infected with M. tuberculosis, followed by treatment with anti-mycobacterial drugs and prolonged rest. ؉ and CD8 ؉ T cells in the lungs of immune mice expressed the activation marker CD69 and could be restimulated to produce gamma interferon (IFN-␥). In contrast, <6% of T cells in the lungs of naive challenged mice were CD69؉ at 1 week postchallenge, and IFN-␥ production was not observed at this time point. CD8؉ T cells from the lungs of both naive and memory mice after challenge were cytotoxic toward M. tuberculosis-infected macrophages. Our data indicate that memory and recall immunity to M. tuberculosis is comprised of both CD4؉ and CD8 ؉ T lymphocytes and that there is a rapid response of both subsets in the lungs following challenge. Control of acute tuberculosis in mice involves participation of CD8ϩ T cells (6,22,37), although a recent publication argues for a more important role for this subset in control of persistent infection (38). Recent studies on the development and activation of mycobacterium-specific CD8 ϩ T cells have indicated that substantial numbers of activated CD8 ϩ T lymphocytes with both cytokine-secreting and cytotoxic functions are present in the lungs during the acute phase of infection in mice (13,19,(33)(34)(35). However, whether this acute response culminates in the development of memory CD8 ϩ T-cell populations that can respond robustly to a secondary Mycobacterium tuberculosis challenge is not clear. It is believed that a proper memory response develops after an infection is cleared. CD8 ϩ T cells play a prominent role during memory immune responses in intracellular bacterial infections with Listeria monocytogenes (11) and Chlamydia pneumoniae (31). In the mouse model and in humans, M. tuberculosis can be a persistent or latent infection. To study the memory response in this infection, it is useful to first reduce or eliminate the bacterial burden in the mouse tissues. It has been reported that the treatment of infected mice with antibiotics leads to the development of an immune response capable of reducing the bacterial burden after challenge (4). The major role in combating bacterial challenge during memory immune responses so far has been attributed exclusively to CD4 ϩ T cells (4). Earlier studies have argued against the participation of memory CD8 ϩ T cells in the recall immune responses in a murine model of tuberculosis (3,4,30). However, the development of a memory CD8 ϩ T-cell population during M. tuberculosis infection is supported by the findings that ...

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Section: Cytotoxic Function Of Memory Cd8 ؉ T Cells Previously We Dmentioning

confidence: 84%

CD8⁺T Cells Participate in the Memory Immune Response toMycobacterium tuberculosis

2001

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“…monocytogenes is the only pathogen known to induce H2-M3-restricted T cells and it will be of great interest to determine whether other bacterial pathogens can do so. Early studies identified apparently MHC-unrestricted CD8 ϩ T cell responses during infection of mice with Mycobacterium bovis bacille Calmette Guérin (33), which probably reflects restriction by a nonpolymorphic presenting molecule such as H2-M3. The ability of H2-M3 to present Ag via both conventional (TAP-dependent) and unconventional (TAP-independent) processing pathways suggests that it may be particularly well suited for presentation of Ag derived from vacuolar bacterial pathogens such as Mycobacterium tuberculosis or Salmonella typhimurium.…”

Section: Discussionmentioning

confidence: 99%

Partially TAP-Independent Protection AgainstListeria monocytogenesby H2-M3-Restricted CD8+ T Cells

Rolph

Kaufmann

2000

The Journal of Immunology

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Effective protection against Listeria monocytogenes requires Ag-specific CD8+ T cells. A substantial proportion of CD8+ T cells activated during L. monocytogenes infection of C57BL/6 mice are restricted by the MHC class Ib molecule H2-M3. In this study, an H2-M3-restricted CD8+ T cell clone specific for a known H2-M3 epitope (fMIGWII) was generated from L. monocytogenes-infected mice. The clone was cytotoxic, produced IFN-γ, and could mediate strong protection against L. monocytogenes when transferred to infected mice. Macrophages pulsed with heat-killed Listeriae presented Ag to the clone in a TAP-independent manner. Both TAP-independent and -dependent processing occurred in vivo, as TAP-deficient mice infected with L. monocytogenes were partially protected by adoptive transfer of the clone. This is the first example of CD8+ T cell-mediated, TAP-independent protection against a pathogen in vivo, confirming the importance of alternative MHC class I processing pathways in the antibacterial immunity.

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“…It is not clear how these cells are protective. One possibility is that the cytotoxic T cells are needed to release bacteria from safe havens inside ineffective macrophages so that they can be phagocytosed by fresh, fully activated monocytes or macrophages (7). Alternatively, studies with human peripheral blood cells in vitro have indicated that lysis of infected macrophages by antigen-specific T cells can directly result in death of the bacteria (17,22).…”

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confidence: 99%

Identification and Characterization of Murine Cytotoxic T Cells That KillMycobacterium tuberculosis

Silva

Lowrie

2000

Infect Immun

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As we seek to develop and evaluate new vaccines against tuberculosis, it is desirable that we understand the mechanisms of protective immunity in our models. Adoptive transfer of protection with hsp65-specific T-cell clones from infected or vaccinated mice into naïve mice had indicated that cytotoxic T cells can make a major contribution to protection. We characterized 28 CD4 ؉ CD8 ؊ and 28 CD4 ؊ CD8 ؉ hsp65-specific T-cell clones derived from infected or vaccinated mice. Half of the CD4 ؉ CD8 ؊ and 64% of the CD4 ؊ CD8 ؉ clones were cytotoxic. Cytotoxicity was associated with high expression of CD44 and gamma interferon production. Most (86%) of the cytotoxic CD4 ؉ CD8 ؊ clones lysed target cells via the Fas-FasL pathway, and most (83%) of the cytotoxic CD4 ؊ CD8 ؉ clones lysed target cells via cytotoxic granules. Only the clones using the granulemediated pathway caused substantial loss of viability of virulent Mycobacterium tuberculosis during lysis of infected macrophages, and the degree of killing closely correlated with the availability of granule marker enzyme activity. Granule-mediated cytotoxicity thus may have a key role in protection against tuberculosis by delivering mycobactericidal granule contents.New vaccines are needed in the fight against tuberculosis (1), but the designing and testing of new vaccines is hampered by our poor understanding of the mechanisms of acquired protective immunity. It is not simply that the key protective antigens have yet to be identified (15); we do not know with certainty what kinds of responses are needed. This knowledge would help both to design vaccines for the best balance of responses and to design clinical tests to monitor or predict vaccine efficacy in the field.Traditionally, protection against tuberculosis has been regarded as due to phagocytosis and killing of Mycobacterium tuberculosis by immunologically activated macrophages and monocytes (12). This is a result of a type 1 cellular response in which gamma interferon (IFN-␥) is produced by antigen-specific T lymphocytes, as distinct from a type 2 response, in which the cells produce interleukin (IL-4) (19). IFN-␥ is the main macrophage-activating factor, and it has been shown to be essential for protection (5,8). However, substantial killing by the activated macrophages or monocytes has been difficult to demonstrate in vitro (4,16,18,24), and there is increasing evidence for a protective role for antigen-specific cytotoxic T lymphocytes, in both murine and human tuberculoses (2, 17, 22). It is not clear how these cells are protective. One possibility is that the cytotoxic T cells are needed to release bacteria from safe havens inside ineffective macrophages so that they can be phagocytosed by fresh, fully activated monocytes or macrophages (7). Alternatively, studies with human peripheral blood cells in vitro have indicated that lysis of infected macrophages by antigen-specific T cells can directly result in death of the bacteria (17, 22). Mycobacterial death can be due to toxic enzymes discharged from lymph...

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Mycobacteria‐reactive Lyt‐2⁺ T cell lines

Cited by 171 publications

References 49 publications

CD8⁺T Cells Participate in the Memory Immune Response toMycobacterium tuberculosis

CD8⁺T Cells Participate in the Memory Immune Response toMycobacterium tuberculosis

Partially TAP-Independent Protection AgainstListeria monocytogenesby H2-M3-Restricted CD8+ T Cells

Identification and Characterization of Murine Cytotoxic T Cells That KillMycobacterium tuberculosis

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Mycobacteria‐reactive Lyt‐2+ T cell lines

Cited by 171 publications

References 49 publications

CD8+T Cells Participate in the Memory Immune Response toMycobacterium tuberculosis

CD8+T Cells Participate in the Memory Immune Response toMycobacterium tuberculosis

Partially TAP-Independent Protection AgainstListeria monocytogenesby H2-M3-Restricted CD8+ T Cells

Identification and Characterization of Murine Cytotoxic T Cells That KillMycobacterium tuberculosis

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Product

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Mycobacteria‐reactive Lyt‐2⁺ T cell lines

CD8⁺T Cells Participate in the Memory Immune Response toMycobacterium tuberculosis

CD8⁺T Cells Participate in the Memory Immune Response toMycobacterium tuberculosis