Protective CD4+ Th1 cell-mediated immunity is reliant upon execution of effector function prior to the establishment of the pathogen niche

Hohman, Leah S.; Mou, Zhirong; Carneiro, Mariângela; Ferland, Gabriel; Kratofil, Rachel M.; Kubes, Paul; Uzonna, Jude; Peters, Nathan C.

doi:10.1371/journal.ppat.1009944

Cited by 13 publications

(8 citation statements)

References 66 publications

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“…Studies in leishmanization models demonstrated that protection upon challenge with L. major parasites is mediated by the TRM cells that help recruit heterogenous cell populations including CD4 + T effector cells and inflammatory monocytes to the site of infection and mediate parasite control 19,20 . Prior studies in leishmanization models also showed the critical role of IFNγ secreting CD4 + CD44 + Ly6C + T effector cells in protection against challenge by virtue of their capacity to mount microbicidal activities immediately after challenge 28,29 . However, since the presence of "ready-to-act" CD4 + CD44 + Ly6C + T effector cells requires a persistent infection of Leishmania parasites, achieving durable protection through safer vaccination methods makes TRM populations more desirable to target.…”

Section: Discussionmentioning

confidence: 98%

Skin resident memory cells generated by the L. major centrin gene deleted parasites mediate protective immune response analogous to leishmanization

Ismail¹,

Karmakar²,

Bhattacharya³

et al. 2021

Preprint

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Leishmaniasis is a vector-borne parasitic disease transmitted through the bite of a sand fly with no available vaccine for humans. Recently, we have developed a live attenuated Leishmania major centrin gene deleted parasite strain (LmCen-/-) that induced protection against a homologous and heterologous challenges. The protection is mediated by IFN-gamma; secreting CD4+ T effector cells and multifunctional T cells, which is analogous to leishmanization. Previously, skin tissue resident memory T cells (TRM cells) were shown to be crucial for host protection in a leishmanization model. In this study, we evaluated generation and function of skin TRM cells following immunization with LmCen-/- parasites and compared those with leishmanization. In the absence of recoverable LmCen-/- parasites, the skin of immunized mice showed functional TRM cells comparable to leishmanized mice. The generation of the skin TRM cells was supported by the induction of cytokines and chemokines essential for their production and survival. Following challenge infection with wild type L. major, TRM cells specific to L. major were rapidly recruited and proliferated at the site of infection in the immunized mice which was similar to leishmanization. Further, upon challenge, CD4+ TRM cells induced higher levels of IFN-gamma; and Granzyme B in the immunized and leishmanized mice than non-immunized mice. Taken together, our studies demonstrate that a genetically modified live attenuated Leishmania vaccine generates functional CD4+ TRM cells that mediate protection and can be a safer alternative to leishmanization.

show abstract

Section: Discussionmentioning

confidence: 98%

Skin resident memory cells generated by the L. major centrin gene deleted parasites mediate protective immune response analogous to leishmanization

Ismail¹,

Karmakar²,

Bhattacharya³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Specifically, it has been demonstrated that protection upon challenge with L. major parasites in healed (i.e., leishmanization) is mediated by the TRM cells that help recruit heterogenous cell populations including CD4 + T-effector cells and inflammatory monocytes to the site of infection and mediate parasite control ( 19 , 20 ). Prior studies in leishmanization models also showed the critical role of IFNγ-secreting CD4 + CD44 + Ly6C + T effector cells in protection against challenge by virtue of their capacity to mount microbicidal activities immediately after challenge ( 28 , 29 ). However, since the presence of “ready-to-act” CD4 + CD44 + Ly6C + T-effector cells requires a persistent infection of Leishmania parasites, achieving durable protection through safer vaccination methods makes TRM populations more desirable to target.…”

Section: Discussionmentioning

confidence: 99%

Leishmania Major Centrin Gene-Deleted Parasites Generate Skin Resident Memory T-Cell Immune Response Analogous to Leishmanization

et al. 2022

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Leishmaniasis is a vector-borne parasitic disease transmitted through the bite of a sand fly with no available vaccine for humans. Recently, we have developed a live attenuated Leishmania major centrin gene-deleted parasite strain (LmCen-/-) that induced protection against homologous and heterologous challenges. We demonstrated that the protection is mediated by IFN (Interferon) γ-secreting CD4+ T-effector cells and multifunctional T cells, which is analogous to leishmanization. In addition, in a leishmanization model, skin tissue-resident memory T (TRM) cells were also shown to be crucial for host protection. In this study, we evaluated the generation and function of skin TRM cells following immunization with LmCen-/- parasites and compared those with leishmanization. We show that immunization with LmCen-/- generated skin CD4+ TRM cells and is supported by the induction of cytokines and chemokines essential for their production and survival similar to leishmanization. Following challenge with wild-type L. major, TRM cells specific to L. major were rapidly recruited and proliferated at the site of infection in the immunized mice. Furthermore, upon challenge, CD4+ TRM cells induce higher levels of IFNγ and Granzyme B in the immunized and leishmanized mice than in non-immunized mice. Taken together, our studies demonstrate that the genetically modified live attenuated LmCen-/- vaccine generates functional CD4+ skin TRM cells, similar to leishmanization, that may play a crucial role in host protection along with effector T cells as shown in our previous study.

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“…Based on this concept, Zhang et al 25 , using a CRISPR genome edited L. major strain ( LmCen −/− ), demonstrated that wildtype L. major infected/healed (leishmanization) and LmCen −/− immunized mice presented high percentage of T CD4 + memory cells producing IFN-γ. The low levels of persistent antigens may be important for maintaining long term protection profile, as the generation of IFN-γ producing CD4 + T effector populations 25 , 78 , despite the difference between the survival profile of parasites used in leishmanization and immunization with attenuated parasites. Independently T CM and skin resident T RM memory T cells were also shown to play a role in protection in L. major mouse models 39 , 79 .…”

Section: Discussionmentioning

confidence: 99%

Deletion of MIF gene from live attenuated LdCen−/− parasites enhances protective CD4+ T cell immunity

Fiuza

Gannavaram

Gaze

et al. 2023

Sci Rep

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Vaccination with live attenuated Leishmania parasites such as centrin deleted Leishmania donovani (LdCen−/−) against visceral leishmaniasis has been reported extensively. The protection induced by LdCen−/− parasites was mediated by both CD4+ and CD8+ T cells. While the host immune mediators of protection are known, parasite determinants that affect the CD4+ and CD8+ T cell populations remain unknown. Parasite encoded inflammatory cytokine MIF has been shown to modulate the T cell differentiation characteristics by altering the inflammation induced apoptosis during contraction phase in experimental infections with Leishmania or Plasmodium. Neutralization of parasite encoded MIF either by antibodies or gene deletion conferred protection in Plasmodium and Leishmania studies. We investigated if the immunogenicity and protection induced by LdCen−/− parasites is affected by deleting MIF genes from this vaccine strain. Our results showed that LdCen−/−MIF−/− immunized group presented higher percentage of CD4+ and CD8+ central memory T cells, increased CD8+ T cell proliferation after challenge compared to LdCen−/− immunization. LdCen−/−MIF−/− immunized group presented elevated production of IFN-γ+ and TNF-α+ CD4+ T cells concomitant with a reduced parasite load in spleen and liver compared to LdCen−/−group following challenge with L. infantum. Our results demonstrate the role of parasite induced factors involved in protection and long-term immunity of vaccines against VL.

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Protective CD4+ Th1 cell-mediated immunity is reliant upon execution of effector function prior to the establishment of the pathogen niche

Cited by 13 publications

References 66 publications

Skin resident memory cells generated by the L. major centrin gene deleted parasites mediate protective immune response analogous to leishmanization

Skin resident memory cells generated by the L. major centrin gene deleted parasites mediate protective immune response analogous to leishmanization

Leishmania Major Centrin Gene-Deleted Parasites Generate Skin Resident Memory T-Cell Immune Response Analogous to Leishmanization

Deletion of MIF gene from live attenuated LdCen−/− parasites enhances protective CD4+ T cell immunity

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