Cutting Edge: CD40–CD40 Ligand Pathway Plays a Critical CD8-Intrinsic and -Extrinsic Role during Rescue of Exhausted CD8 T Cells

Bhadra, Rajarshi; Gigley, Jason P.; Khan, Imtiaz Ali

doi:10.4049/jimmunol.1102319

Cited by 55 publications

(80 citation statements)

References 13 publications

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“…Consistent with our data, it has been reported previously that PD-1 ligation with its ligand inhibits not only the PI3K-Akt pathway but also the MAPK1 pathway in human T cells activated with anti-CD3 mAb [40]. Another study has also shown that blockade of PD-1 and B7-H1 interaction rescues exhausted CD8 T cells via up-regulation of the CD40 -CD40L ligation pathway [41]. Taken together, these results suggest that downstream of PD-1, in T cells and DCs, is regulated by the common signaling pathways; PD-1 induced in DCs, as well as T cells, acts as a negative-feedback mechanism for the maintenance of immune homeostasis.…”

Section: Discussionsupporting

confidence: 93%

Negative role of inducible PD-1 on survival of activated dendritic cells

Park

Namkoong

Doh

et al. 2013

Journal of Leukocyte Biology

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PD-1 is a well-established negative regulator of T cell responses by inhibiting proliferation and cytokine production of T cells via interaction with its ligands, B7-H1 (PD-L1) and B7-DC (PD-L2), expressed on non-T cells. Recently, PD-1 was found to be expressed in innate cells, including activated DCs, and plays roles in suppressing production of inflammatory cytokines. In this study, we demonstrate that PD-1 KO DCs exhibited prolonged longevity compared with WT DCs in the dLNs after transfer of DCs into hind footpads. Interestingly, upon LPS stimulation, WT DCs increased the expression of PD-1 and started to undergo apoptosis. DCs, in spleen of LPS-injected PD-1 KO mice, were more resistant to LPS-mediated apoptosis in vivo than WT controls. Moreover, treatment of blocking anti-PD-1 mAb during DC maturation resulted in enhanced DC survival, suggesting that PD-1:PD-L interactions are involved in DC apoptosis. As a result, PD-1-deficient DCs augmented T cell responses in terms of antigen-specific IFN-γ production and proliferation of CD4 and CD8 T cells to a greater degree than WT DCs. Moreover, PD-1 KO DCs exhibited increased MAPK1 and CD40-CD40L signaling, suggesting a possible mechanism for enhanced DC survival in the absence of PD-1 expression. Taken together, our findings further extend the function of PD-1, which plays an important role in apoptosis of activated DCs and provides important implications for PD-1-mediated immune regulation.

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Section: Discussionsupporting

confidence: 93%

Negative role of inducible PD-1 on survival of activated dendritic cells

Park

Namkoong

Doh

et al. 2013

Journal of Leukocyte Biology

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“…This makes a pathogen-specific study of polyfunctionality and host morbidity and mortality critical for determining whether gain or loss of polyfunctionality is linked to pathogen clearance. In contrast, in the Toxoplasma model, as we have previously demonstrated [13,36] and further reiterated in the current study, loss of polyfunctional CD8 + T cells is strongly associated with PD-1-mediated CD8 + exhaustion and recrudescence of disease. Moreover αPD-L1 treatment not only upregulated polyfunctional CD8 + T-cell response but also prevented parasite reactivation.…”

Section: Discussionsupporting

confidence: 75%

PD-1–Mediated Attrition of Polyfunctional Memory CD8+ T Cells in Chronic Toxoplasma Infection

Bhadra

Gigley

Khan

2012

The Journal of Infectious Diseases

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We reported earlier that during chronic toxoplasmosis CD8 + T cells become functionally exhausted with concomitant PD-1 upregulation, leading to eventual host mortality. However, how immune exhaustion specifically mediates attrition of CD8 polyfunctionality, a hallmark of potent T-cell response, during persistent infections has not been addressed. In this study, we demonstrate that PD-1 is preferentially expressed on polyfunctional memory CD8 + T cells, which renders them susceptible to apoptosis. In vitro blockade of the PD-1-PD-L1 pathway dramatically reduces apoptosis of polyfunctional and interferon γ + /granzyme B − memory but not effector CD8 + T cells. In summary, the present report underscores the critical role of the PD-1-PD-L1 pathway in mediating attrition of this important CD8 + T-cell subset and addresses the mechanistic basis of how αPD-L1 therapy reinvigorates polyfunctional CD8 response during chronic infections. The conclusions of this study can have profound immunotherapeutic implications in combating recrudescent toxoplasmosis as well other chronic infections. Effective

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“…4E and F ϩ T cell recruitment can potentially result in unaltered numbers of CD8 ϩ T cells in these recipients. Hence, to definitively address if control of parasite reactivation had any effect on in situ proliferation, CD8 ϩ T cells were assessed for Ki-67, a widely used maker for cell proliferation (16,17). As shown in Fig.…”

Section: Cd8 ؉ T Cells From Immune Donors Fail To Rescue the Endogenomentioning

confidence: 99%

“…Nevertheless, as our data clearly demonstrate, immunotherapy with immune CD8 ϩ T cells is not an appropriate solution for the rescue of dysfunctional CD8 ϩ T cells. Recent studies from our group have demonstrated that anti-PD-L1 treatment of chronically infected mice augments the levels of CD8 ϩ T cell-expressed Eomes (16,17), a T-box family transcription factor critical for memory development (50). Taking this into consideration, it will be interesting to determine if adoptive transfer of retrovirally transfected Eomes overexpressing CD8 ϩ T cells is able to elicit a more robust and long-lasting outcome.…”

Section: Cd8mentioning

confidence: 99%

“…Recent studies from our laboratory have reported that chronic infection with T. gondii in the genetically susceptible C57BL/6 mouse results in a graded increase in the level of the inhibitory receptor, PD-1 (Programmed Death-1), on CD8 ϩ T cells (16)(17)(18)(19)(20). This leads to elevated CD8 apoptosis and progressive attrition of their functionality in terms of IFN-␥ production.…”

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confidence: 99%

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Donor CD8⁺T Cells Prevent Toxoplasma gondii De-Encystation but Fail To Rescue the Exhausted Endogenous CD8⁺T Cell Population

2013

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Functional exhaustion of CD8؉ T cells due to increased expression of inhibitory molecule PD-1 (Programmed Death-1) causes reactivation of latent disease during later phases of chronic toxoplasmosis. Onset of disease recrudescence results in decreased parasite cyst burden concomitant with parasites undergoing stage conversion from a primarily encysted, quiescent bradyzoite to a fast-replicating, highly motile tachyzoite. Thus, reduced cyst burden is one of the early hallmarks of disease recrudescence. This was further validated by depleting gamma interferon (IFN-␥), a cytokine known to control latent toxoplasmosis, in chronically infected prerecrudescent mice. Since CD8 ؉ T cells (an important source of IFN-␥) lose their functionality during the later phases of chronic toxoplasmosis, we next examined if adoptive transfer of functional CD8 ؉ T cells from acutely infected donors to the chronically infected prerecrudescent hosts could impede parasite de-encystation and rescue exhausted CD8 ؉ T cells. While the transfer of immune CD8؉ T cells temporarily restricted the breakdown of cysts, the exhausted endogenous CD8 ؉ T cell population was not rescued. Over time, the donor population got deleted, resulting in parasite de-encystation and host mortality. Considering that donor CD8 ؉ T cells fail to become long-lived, one of the cardinal features of memory CD8 ؉ T cells, it bears the implication that memory CD8 differentiation is impaired during chronic toxoplasmosis. Moreover, our data strongly suggest that while adoptive immunotherapy can prevent parasite de-encystation transiently, reduced antigen burden in the chronic phase by itself is insufficient for rescue of exhausted CD8 ؉ T cells. The conclusions of this study have profound ramifications in designing immunotherapeutics against chronic toxoplasmosis.

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Cutting Edge: CD40–CD40 Ligand Pathway Plays a Critical CD8-Intrinsic and -Extrinsic Role during Rescue of Exhausted CD8 T Cells

Cited by 55 publications

References 13 publications

Negative role of inducible PD-1 on survival of activated dendritic cells

Negative role of inducible PD-1 on survival of activated dendritic cells

PD-1–Mediated Attrition of Polyfunctional Memory CD8+ T Cells in Chronic Toxoplasma Infection

Donor CD8⁺T Cells Prevent Toxoplasma gondii De-Encystation but Fail To Rescue the Exhausted Endogenous CD8⁺T Cell Population

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Cutting Edge: CD40–CD40 Ligand Pathway Plays a Critical CD8-Intrinsic and -Extrinsic Role during Rescue of Exhausted CD8 T Cells

Cited by 55 publications

References 13 publications

Negative role of inducible PD-1 on survival of activated dendritic cells

Negative role of inducible PD-1 on survival of activated dendritic cells

PD-1–Mediated Attrition of Polyfunctional Memory CD8+ T Cells in Chronic Toxoplasma Infection

Donor CD8+T Cells Prevent Toxoplasma gondii De-Encystation but Fail To Rescue the Exhausted Endogenous CD8+T Cell Population

Contact Info

Product

Resources

About

Donor CD8⁺T Cells Prevent Toxoplasma gondii De-Encystation but Fail To Rescue the Exhausted Endogenous CD8⁺T Cell Population