Macrophage – T cell interaction in experimental mycobacterial infection. Selective regulation of co‐stimulatory molecules on <i>Mycobacterium</i>‐ infected macrophages and its implication in the suppression of cell‐mediated immune response

Saha, Bhaskar; Das, Gobardhan; Vohra, Harpreet; Ganguly, Nirmal Kumar; Mishra, Gyan C.

doi:10.1002/eji.1830241108

Cited by 84 publications

(58 citation statements)

References 38 publications

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“…There is considerable controversy with respect to the influence of BCG on immune responses with some suggesting that BCG is a potent adjuvant for the induction of the T cell response to recombinant Ags (33,34), but on the other hand others have associated BCG with suppressive effects (35)(36)(37)(38)(39)(40)(41). Similar suppressive effects have been reported in ST infection models (42).…”

Section: Discussionmentioning

confidence: 84%

IFN-γ Induces the Erosion of Preexisting CD8 T Cell Memory during Infection with a Heterologous Intracellular Bacterium

Dudani

Krishnan

Sad

2008

The Journal of Immunology

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Memory T cells are critical for the control of intracellular pathogens and require few signals for maintenance; however, erosion of established preexisting memory CD8+ T cells has been shown to occur during infection with heterologous viral infections. We evaluated whether this also occurs during infection with various intracellular bacteria and what mechanisms may be involved. We demonstrate that erosion of established memory is also induced during infection of mice with various intracellular bacteria, such as Listeria monocytogenes, Salmonella typhimurium, and Mycobacterium bovis (bacillus Calmette-Guérin). The extent of erosion of established CD8+ T cell memory was dependent on the virulence of the heterologous pathogen, not persistence. Furthermore, when antibiotics were used to comprehensively eliminate the heterologous pathogen, the numbers of memory CD8+ T cells were not restored, indicating that erosion of preexisting memory CD8+ T cells was irreversible. Irrespective of the initial numbers of memory CD8+ T cells, challenge with the heterologous pathogen resulted in a similar extent of erosion of memory CD8+ T cells, suggesting that cellular competition was not responsible for erosion. After challenge with the heterologous pathogen, effector memory CD8+ T cells were rapidly eliminated. More importantly, erosion of preexisting memory CD8+ T cells was abrogated in the absence of IFN-γ. These studies help reveal the paradoxical role of IFN-γ. Although IFN-γ promotes the control of intracellular bacterial replication during primary infection, this comes at the expense of erosion of preexisting memory CD8+ T cells in the wake of infection with heterologous pathogens.

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Section: Discussionmentioning

confidence: 84%

IFN-γ Induces the Erosion of Preexisting CD8 T Cell Memory during Infection with a Heterologous Intracellular Bacterium

Dudani

Krishnan

Sad

2008

The Journal of Immunology

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“…This anergy is characterized by a proliferative block and decreased IL-2 secretion and production (29) and has been attributed to both suppressor T cells and/or inhibitory macrophages via the production of inhibitory mediators like IL-6 (34), transforming growth factor beta (13), and NO (36). A similar phenomenon is seen with some preparations of mycobacterial antigens, like purified protein derivative, particularly at high infection burdens in both mice and humans (reviewed in reference 7).…”

Section: Discussionmentioning

confidence: 92%

Mycobacterium bovisBCG-Infected Mice Are More Susceptible to Staphylococcal Enterotoxin B-Mediated Toxic Shock than Uninfected Mice despite Reduced In Vitro Splenocyte Responses to Superantigens

et al. 2002

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Type 1 T-cell responses against intracellular pathogens play a crucial role in mediating protection. We examined whether the induction of a strong type 1 T-cell response during a chronic bacterial infection influences responses to superantigens capable of inducing acute shock. Intravenous infection of mice with Mycobacterium bovis BCG appeared to induce a progressive anergy towards staphylococcal enterotoxin B (SEB) and towards antigen preparation of BCG (BCG-Ag) itself, based on diminished gamma interferon (IFN-␥) production by SEB-and BCG-Ag-stimulated splenocytes from infected mice. In contrast to these in vitro results, injection of SEB into BCG-infected mice led to a dramatic increase in the serum IFN-␥ levels and the death of infected but not of control mice. In vitro hyporesponsiveness towards SEB and BCG-Ag occurred only with unfractionated splenocyte cultures, as purified T cells from infected mice produced higher levels of IFN-␥. Hyporesponsiveness towards SEB and BCG-Ag in unfractionated splenocyte cultures was not due to suppressive antigen-presenting cells (APCs), as APCs from infected mice stimulated higher levels of IFN-␥ from purified T cells. The diminished IFN-␥ levels observed with bulk splenocytes appear to be due to changes in the T-cell-to-APC ratio that result in a decreased proportion of T cells, coupled to reduced proliferative responses and an increased susceptibility of effector T cells to activation-induced cell death in vitro. Our results indicate that the reported phenomena of T-cell anergy during mycobacterial infection may be an in vitro consequence of the development of a strong type 1 response in vivo. CD4ϩ -and CD8 ϩ -T-cell activation is important for protection against infectious diseases (23). Under extreme polarizing conditions (such as chronic infections), CD4ϩ T cells differentiate into type 1 (producing interleukin 2 [IL-2] and gamma interferon [IFN-␥]) or type 2 (producing IL-4, IL-5, and IL-13) effectors and, once generated, mediate differential protection depending on the type of pathogen and the strain of mouse used (23). CD8 ϩ T cells, on the other hand, are primarily involved in protection against intracellular pathogens, particularly those that replicate in the cytoplasm of the host cell (38).Mycobacterium bovis BCG is a facultative intracellular bacterium that causes chronic infections in susceptible hosts. In mice, infection with BCG results in the development of splenomegaly in the first 4 weeks of disease, with increased accumulation of splenocytes during that time (25). Infection also leads to the development of a BCG-specific IFN-␥ response at both the CD4 ϩ -and CD8 ϩ -T-cell levels (32). As with other pathogenic mycobacteria, BCG infection has been reported to induce T-cell anergy, particularly at higher bacterial burdens (25).Superantigens hyperstimulate T cells by acting as a bridge between superantigen-restricted V␤-containing T-cell receptors (TCRs) and major histocompatibility complex (MHC) class II molecules, resulting in a high responder frequency a...

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“…There is considerable controversy with respect to the influence of BCG on immune responses with some suggesting that BCG is a potent adjuvant for the induction of T cell response to recombinant Ags (28,42), but, on the other hand, others have associated BCG with suppressive effects (43)(44)(45)(46)(47)(48)(49). Our previous observations (26) and results presented here support BCG as a potent inducer of CD8 ϩ T cell responses (IFN-␥ and CTL activity) for a prolonged period of time.…”

Section: Discussionmentioning

confidence: 99%

Cross-Reactive Antigen Is Required to Prevent Erosion of Established T Cell Memory and Tumor Immunity: A Heterologous Bacterial Model of Attrition

Smith

Dudani

Pedras-Vasconcelos

et al. 2002

The Journal of Immunology

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Induction and maintenance of T cell memory is critical for the control of intracellular pathogens and tumors. Memory T cells seem to require few “maintenance signals,” though often such studies are done in the absence of competing immune challenges. Conversely, although attrition of CD8+ T cell memory has been characterized in heterologous viral models, this is not the case for bacterial infections. In this study, we demonstrate attrition of T cell responses to the intracellular pathogen Listeria monocytogenes (LM) following an immune challenge with a second intracellular bacterium, Mycobacterium bovis (bacillus Calmette-Guérin, BCG). Mice immunized with either LM or recombinant LM (expressing OVA; LM-OVA), develop a potent T cell memory response. This is reflected by peptide-specific CTL, IFN-γ production, and frequency of IFN-γ-secreting T cells to native or recombinant LM Ags. However, when the LM-infected mice are subsequently challenged with BCG, there is a marked reduction in the LM-specific T cell responses. These reductions are directly attributable to the effects on CD4+ and CD8+ T cells and the data are consistent with a loss of LM-specific T cells, not anergy. Attrition of the Ag (OVA)-specific T cell response is prevented when LM-OVA-immunized mice are challenged with a subsequent heterologous pathogen (BCG) expressing OVA, demonstrating memory T cell dependence on Ag. Although the reduction of the LM-specific T cell response did not impair protection against a subsequent LM rechallenge, for the first time, we show that T cell attrition can result in the reduction of Ag-specific antitumor (B16-OVA) immunity previously established with LM-OVA immunization.

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Macrophage – T cell interaction in experimental mycobacterial infection. Selective regulation of co‐stimulatory molecules on Mycobacterium‐ infected macrophages and its implication in the suppression of cell‐mediated immune response

Cited by 84 publications

References 38 publications

IFN-γ Induces the Erosion of Preexisting CD8 T Cell Memory during Infection with a Heterologous Intracellular Bacterium

IFN-γ Induces the Erosion of Preexisting CD8 T Cell Memory during Infection with a Heterologous Intracellular Bacterium

Mycobacterium bovisBCG-Infected Mice Are More Susceptible to Staphylococcal Enterotoxin B-Mediated Toxic Shock than Uninfected Mice despite Reduced In Vitro Splenocyte Responses to Superantigens

Cross-Reactive Antigen Is Required to Prevent Erosion of Established T Cell Memory and Tumor Immunity: A Heterologous Bacterial Model of Attrition

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