T Cells from Programmed Death-1 Deficient Mice Respond Poorly to Mycobacterium tuberculosis Infection

Tousif, Sultan; Singh, Yogesh; Prasad, D. Vijaya Raghava; Sharma, Pawan; Kaer, Luc Van; Das, Gobardhan

doi:10.1371/journal.pone.0019864

Cited by 79 publications

(79 citation statements)

References 47 publications

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“…PD-1 is a B7-family protein expressed on exhausted T cells and is responsible for loss of effective control in chronic infection and cancer (38). In contrast, mice lacking PD-1 are more susceptible to M. tuberculosis infection (39)(40)(41). KLRG1 expression is a surrogate marker of terminally differentiated, short-lived effector CD8 T cells in inflammation and viral infection models (42).…”

Section: Discussionmentioning

confidence: 99%

Protective CD4 T Cells Targeting Cryptic Epitopes of Mycobacterium tuberculosis Resist Infection-Driven Terminal Differentiation

Woodworth

Aagaard

Hansen

et al. 2014

The Journal of Immunology

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CD4 T cells are crucial to the control of Mycobacterium tuberculosis infection and are a key component of current vaccine strategies. Conversely, immune-mediated pathology drives disease, and recent evidence suggests that adaptive and innate responses are evolutionarily beneficial to M. tuberculosis. We compare the functionality of CD4 T cell responses mounted against dominant and cryptic epitopes of the M. tuberculosis 6-kDa early secreted Ag (ESAT-6) before and postinfection. Protective T cells against cryptic epitopes not targeted during natural infection were induced by vaccinating mice with a truncated ESAT-6 protein, lacking the dominant epitope. The ability to generate T cells that recognize multiple cryptic epitopes was MHC-haplotype dependent, including increased potential via heterologous MHC class II dimers. Before infection, cryptic epitope–specific T cells displayed enhanced proliferative capacity and delayed cytokine kinetics. After aerosol M. tuberculosis challenge, vaccine-elicited CD4 T cells expanded and recruited to the lung. In chronic infection, dominant epitope–specific T cells developed a terminal differentiated KLRG1+/PD-1lo surface phenotype that was significantly reduced in the cryptic epitope–specific T cell populations. Dominant epitope-specific T cells in vaccinated animals developed into IFN-γ– and IFN-γ,TNF-α–coproducing effector cells, characteristic of the endogenous response. In contrast, cryptic epitope–specific CD4 T cells maintained significantly greater IFN-γ+TNF-α+IL-2+ and TNF-α+IL-2+ memory-associated polyfunctionality and enhanced proliferative capacity. Vaccine-associated IL-17A production by cryptic CD4 T cells was also enhanced, but without increased neutrophilia/pathology. Direct comparison of dominant/cryptic epitope–specific CD4 T cells within covaccinated mice confirmed the superior ability of protective cryptic epitope–specific T cells to resist M. tuberculosis infection–driven T cell differentiation.

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Section: Discussionmentioning

confidence: 99%

Protective CD4 T Cells Targeting Cryptic Epitopes of Mycobacterium tuberculosis Resist Infection-Driven Terminal Differentiation

Woodworth

Aagaard

Hansen

et al. 2014

The Journal of Immunology

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“…Moreover, infection of PD-1 KO mice with BCG leads to enhanced T-cell responses and bacterial control rather than immunopathology (Sakai et al 2010). However, rather than displaying enhanced protection, PD-1 knockout mice succumb rapidly on exposure to low doses of virulent Mtb (Lázár-Molnár et al 2010;Barber et al 2011;Tousif et al 2011). It was found that PD-1 KO mice have greatly increased numbers of I-A b ESAT-6 1 -20 tetramer-binding CD4 T cells in their lungs and that transient depletion of CD4 T cells in the first month of infection prevented the severe tissue destruction and death of the PD-1 KO mice .…”

Section: Negative Regulation Of T-cell Responses During Tuberculosismentioning

confidence: 99%

Innate and Adaptive Cellular Immune Responses toMycobacterium tuberculosisInfection

Mayer‐Barber

Barber

2015

Cold Spring Harb Perspect Med

115

101

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“…Curiously, recent studies showed that PD-1 −/− mice exhibited an altered response to infection with mycobacteria, characterized by uncontrolled bacterial burden; massive production of cytokines, termed "cytokine storm"; and early death (23)(24)(25). We wondered if this unique response of PD-1 −/− mice to mycobacteria contributed to their Th response in EAE.…”

mentioning

confidence: 99%

Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response

Rui

Honjo

Chikuma

2013

Proc. Natl. Acad. Sci. U.S.A.

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Programmed cell death 1 (PD-1) is an inhibitory coreceptor on immune cells and is essential for self-tolerance because mice genetically lacking PD-1 (PD-1 −/− ) develop spontaneous autoimmune diseases. PD-1 −/− mice are also susceptible to severe experimental autoimmune encephalomyelitis (EAE), characterized by a massive production of effector/memory T cells against myelin autoantigen, the mechanism of which is not fully understood. We found that an increased primary response of PD-1 −/− mice to heat-killed mycobacteria (HKMTB), an adjuvant for EAE, contributed to the enhanced production of T-helper 17 (Th17) cells. Splenocytes from HKMTB-immunized, lymphocyte-deficient PD-1 −/− recombination activating gene (RAG)2 −/− mice were found to drive antigen-specific Th17 cell differentiation more efficiently than splenocytes from HKMTB-immunized PD-1 +/+ RAG2 −/− mice. This result suggested PD-1's involvement in the regulation of innate immune responses. Mice reconstituted with PD-1 −/− RAG2 −/− bone marrow and PD-1 +/+ CD4 + T cells developed more severe EAE compared with the ones reconstituted with PD-1 +/+ RAG2 −/− bone marrow and PD-1 +/+ CD4 + T cells. We found that upon recognition of HKMTB, CD11b + macrophages from PD-1 −/− mice produced very high levels of IL-6, which helped promote naive CD4 + T-cell differentiation into IL-17-producing cells. We propose a model in which PD-1 negatively regulates antimycobacterial responses by suppressing innate immune cells, which in turn prevents autoreactive T-cell priming and differentiation to inflammatory effector T cells.autoimmunity | inflammation

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T Cells from Programmed Death-1 Deficient Mice Respond Poorly to Mycobacterium tuberculosis Infection

Cited by 79 publications

References 47 publications

Protective CD4 T Cells Targeting Cryptic Epitopes of Mycobacterium tuberculosis Resist Infection-Driven Terminal Differentiation

Protective CD4 T Cells Targeting Cryptic Epitopes of Mycobacterium tuberculosis Resist Infection-Driven Terminal Differentiation

Innate and Adaptive Cellular Immune Responses toMycobacterium tuberculosisInfection

Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response

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