Role of CD4 T Cell Help and Costimulation in CD8 T Cell Responses During <i>Listeria monocytogenes</i> Infection

Shedlock, Devon J.; Whitmire, Jason K.; Tan, Joyce T.; MacDonald, Andrew S.; Ahmed, Rafi; Shen, Hao

doi:10.4049/jimmunol.170.4.2053

Cited by 152 publications

(145 citation statements)

References 77 publications

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“…It might therefore be possible that HKLM immunization does not induce sufficient 4-1BBL up-regulation on CD11c hi DC to fully activate CD8 + T cells. In support of this, a recent study using 4-1BBL-deficient mice suggested impaired CD8 + T cell activation following L. monocytogenes infection [23].…”

Section: Discussionmentioning

confidence: 76%

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Distinct in vivo dendritic cell activation by live versus killed Listeria monocytogenes

et al. 2005

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Immunization of mice with live or heat-killed Listeria monocytogenes (HKLM) efficiently primes pathogen-specific CD8 + T cells. T lymphocytes primed by HKLM, however, undergo attenuated proliferation and do not fully differentiate. Thus, only infection with live bacteria induces long-term, CD8 + T cell-mediated protective immunity. In this study we demonstrate that live and heat-killed bacteria, while both associating with Mac-3 + CD11b hi cells, localize to distinct splenic areas following intravenous inoculation. While HKLM localize to the marginal zone and the splenic red pulp, live L. monocytogenes are carried to the T cell zone of splenic white pulp. Despite these differences, in vivo depletion of CD11c-expressing cells prevents priming of naive T cells by either HKLM or live L. monocytogenes. Analysis of CD11c hi dendritic cells (DC) reveals that infection with live L. monocytogenes induces higher levels of CD40, CD80 and CD86 expression than immunization with HKLM. Our results suggest that CD8 + T cell priming following HKLM immunization or live infection is mediated by DC and that the disparate outcomes of priming can be attributed to suboptimal conditioning of DC in the absence of live, cytosol-invasive bacteria.

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Section: Discussionmentioning

confidence: 76%

“…6) supports the hypothesis that killed bacteria do not fully activate DC. It has been shown in vitro that live bacteria are far more potent in activating bone marrow-derived DC than are HKLM [23]. This favors the idea that HKLM and live bacteria differentially activate DC in vivo.…”

Section: Discussionmentioning

confidence: 98%

Distinct in vivo dendritic cell activation by live versus killed Listeria monocytogenes

et al. 2005

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“…The costimulatory role of TNFR2 during LM infection appears similar to CD28: CD28 Ϫ/Ϫ mice possess reduced LM-specific CD8 T cell responses, compared with WT mice, but differentiation into effector T cells is intact (11,12). Moreover, CD28 Ϫ/Ϫ mice exhibited increased susceptibility to LM as evidenced by persistent bacterial load even up to day 7 p.i.…”

Section: Discussionmentioning

confidence: 84%

“…3 CD28-deficient mice have reduced LM-specific CD8 T cell responses, compared with wild-type (WT) mice, but differentiation into effector and memory T cells appears intact (11), suggesting that CD28 sets a critical threshold for the accumulation of LM-specific CD8 T cells. Mice that lack CD137 ligand (4-1BB ligand) also display diminished activation of CD8 T cells, compared with WT mice (12). Thus, costimulation mediated by members of two distinct superfamilies of receptors provides multiple checkpoints in the differentiation program that confers flexibility in the adaptive immune response.…”

mentioning

confidence: 99%

TNF Receptor Type 2 (p75) Functions as a Costimulator for Antigen-Driven T Cell Responses In Vivo

Kim

Priatel

Teh

et al. 2006

The Journal of Immunology

142

130

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Naive T cells require costimulation for robust Ag-driven differentiation and survival. Members of the TNFR family have been shown to provide costimulatory signals conferring survival at distinct phases of the T cell response. In this study, we show that CD4 and CD8 T cells depend on TNFR type 2 (p75) for survival during clonal expansion, allowing larger accumulation of effector cells and conferring protection from apoptosis for a robust memory pool in vivo. We demonstrate using the MHC class I-restricted 2C TCR and MHC class II-restricted AND TCR transgenic systems that TNFR2 regulates the threshold for clonal expansion of CD4 and CD8 T cell subsets in response to cognate Ag. Using a novel recombinant Listeria monocytogenes (rLM) expressing a secreted form of the 2C agonist peptide (SIY) to investigate the role of TNFR2 for T cell immunity in vivo, we found that TNFR2 controls the survival and accumulation of effector cells during the primary response. TNFR2−/− CD8 T cells exhibit loss of protection from apoptosis that is correlated with diminished survivin and Bcl-2 expression. Null mutant mice were more susceptible to rLM-SIY challenge at high doses of primary infection, correlating with impaired LM-specific T cell response in the absence of TNFR2-mediated costimulation. Moreover, the resulting memory pools specific for SIY and listeriolysin O epitopes derived from rLM-SIY were diminished in TNFR2−/− mice. Thus, examination of Ag-driven T cell responses revealed a hitherto unknown costimulatory function for TNFR2 in regulating T cell survival during the differentiation program elicited by intracellular pathogen in vivo.

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“…Such a cell population, which could be re-expanded out of a small pool of central memory T cells within a short period of time after antigen reencounter, may not need to be maintained at high frequencies. Three observations in the bacterial infection model support this hypothesis: (1) Despite decreasing numbers of bacteria-specific CD4 + memory T cells, the quality of protective immunity is not negatively affected; even after complete depletion of CD4 + T cells following primary infection, CD8 + Listeria-specific memory T cells are maintained and mediate effective protective immunity [32]. Interestingly, depletion of CD4 + T cells actually enhances the CD8 + memory T cell response [33].…”

Section: Discussionmentioning

confidence: 90%

Differences in maintenance of CD8⁺ and CD4⁺ bacteria‐specific effector‐memory T cell populations

et al. 2003

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Our knowledge about the kinetics and dynamics of complex pathogen-specific CD8 + T cell responses and the in vivo development of CD8 + memory T cells has increased substantially over the past years; in comparison, relatively little is known about the CD4 + T cell compartment. We monitored and directly compared the phenotypical changes of pathogen (Listeria monocytogenes)-specific CD8 + and CD4 + T cell responses under conditions leading to effective and long-lasting protective immunity. We found that the general kinetics of bacteriaspecific CD8 + and CD4 + T cells during the effector and post-effector phases are synchronized. However, later during the memory phase, CD8 + and CD4 + T cell populations differ substantially. Whereas CD8 + memory T cell populations with immediate effector function are readily detectable in lymphoid and non-lymphoid tissues and remain remarkably stable in size, antigen-specific CD4 + effector-memory T cells decline continuously in frequency over time. These findings have important implications for the better understanding of the in vivo development of protective immunity towards intracellular pathogens.

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Role of CD4 T Cell Help and Costimulation in CD8 T Cell Responses During Listeria monocytogenes Infection

Cited by 152 publications

References 77 publications

Distinct in vivo dendritic cell activation by live versus killed Listeria monocytogenes

Distinct in vivo dendritic cell activation by live versus killed Listeria monocytogenes

TNF Receptor Type 2 (p75) Functions as a Costimulator for Antigen-Driven T Cell Responses In Vivo

Differences in maintenance of CD8⁺ and CD4⁺ bacteria‐specific effector‐memory T cell populations

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Role of CD4 T Cell Help and Costimulation in CD8 T Cell Responses During Listeria monocytogenes Infection

Cited by 152 publications

References 77 publications

Distinct in vivo dendritic cell activation by live versus killed Listeria monocytogenes

Distinct in vivo dendritic cell activation by live versus killed Listeria monocytogenes

TNF Receptor Type 2 (p75) Functions as a Costimulator for Antigen-Driven T Cell Responses In Vivo

Differences in maintenance of CD8+ and CD4+ bacteria‐specific effector‐memory T cell populations

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Differences in maintenance of CD8⁺ and CD4⁺ bacteria‐specific effector‐memory T cell populations