M-CSF directs myeloid and NK cell differentiation to protect from CMV after HCT
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ABSTRACT:
SUBMITTER: Dr. Prashanth, K. Kandalla
PROVIDER: S-SCDT-10_15252-EMMM_202317694 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:Therapies reconstituting autologous antiviral immunocompetence may represent an important prophylaxis and treatment for immunosuppressed individuals. Following hematopoietic cell transplantation (HCT), patients are susceptible to Herpesviridae including cytomegalovirus (CMV). We show in a murine model of HCT that macrophage colony-stimulating factor (M-CSF) promoted rapid antiviral activity and protection from viremia caused by murine CMV. M-CSF given at transplantation stimulated sequential myeloid and natural killer (NK) cell differentiation culminating in increased NK cell numbers, production of granzyme B and interferon-γ. This depended upon M-CSF-induced myelopoiesis leading to IL15Rα-mediated presentation of IL-15 on monocytes, augmented by type I interferons from plasmacytoid dendritic cells. Demonstrating relevance to human HCT, M-CSF induced myelomonocytic IL15Rα expression and numbers of functional NK cells in G-CSF-mobilized hematopoietic stem and progenitor cells. Together, M-CSF-induced myelopoiesis triggered an integrated differentiation of myeloid and NK cells to protect HCT recipients from CMV. Thus, our results identify a rationale for the therapeutic use of M-CSF to rapidly reconstitute antiviral activity in immunocompromised individuals, which may provide a general paradigm to boost innate antiviral immunocompetence using host-directed therapies.
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Project description:Cytomegalovirus (CMV) is a globally ubiquitous pathogen with a seroprevalence of approximately 50% in the United Kingdom. CMV infection induces expansion of immunosenescent T cell and NK cell populations, with these cells demonstrating lower responsiveness to activation and reduced functionality upon infection and vaccination. In this study, we found that CMV+ participants had normal T cell responses after a single-dose or homologous vaccination with the viral vector chimpanzee adenovirus developed by the University of Oxford (ChAdOx1). CMV seropositivity was associated with reduced induction of IFN-γ-secreting T cells in a ChAd-Modified Vaccinia Ankara (ChAd-MVA) viral vector vaccination trial. Analysis of participants receiving a single dose of ChAdOx1 demonstrated that T cells from CMV+ donors had a more terminally differentiated profile of CD57+PD1+CD4+ T cells and CD8+ T cells expressing less IL-2Rα (CD25) and fewer polyfunctional CD4+ T cells 14 days after vaccination. NK cells from CMV-seropositive individuals also had a reduced activation profile. Overall, our data suggest that although CMV infection enhances immunosenescence of T and NK populations, it does not affect antigen-specific T cell IFN-γ secretion or antibody IgG production after vaccination with the current ChAdOx1 nCoV-19 vaccination regimen, which has important implications given the widespread use of this vaccine, particularly in low- and middle-income countries with high CMV seroprevalence.
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Project description:Ly49G2 (G2+) NK cells mediate murine (M)CMV resistance in MHC D(k) -expressing mice. Bone marrow transplantation (BMT) studies revealed that G2+ NK cell-mediated MCMV resistance requires D(k) in both hematopoietic and nonhematopoietic cells. As a Ly49G2 ligand, D(k) in both cell lineages may contribute to lysis of virus-infected cells. Alternatively, cellular differences in self-MHC D(k) may have affected NK-cell education, and consequently NK cell-mediated viral clearance. We investigated the D(k) -licensing effect on BM-derived NK cells in BMT recipients by analyzing cytokines, cytotoxicity and MCMV resistance. In BMT recipients with lineage-restricted D(k) , G2+ NK-cell reactivity and cytotoxicity was diminished in comparison to BMT recipients with self-MHC in all cells. Reduced G2+ NK-mediated MCMV resistance in BMT recipients with lineage-restricted self-MHC indicates that licensing of G2+ NK cells is related to NK-cell reactivity and viral control. Titrating donor BM with self-MHC-bearing hematopoietic cells, as well as adoptive transfer of mature G2+ NK cells into BMT recipients with self-MHC in non-hematopoietic cells only, enhanced NK-cell licensing and rescued MCMV resistance. This disparate self-MHC NK-cell education model would suggest that inadequately licensed NK cells corresponded to inefficient viral sensing and clearance.
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Project description:The worldwide struggle against the coronavirus disease 2019 (COVID-19) as a public health crisis continues to sweep across the globe. Up to now, effective antiviral treatment against COVID-19 is not available. Therefore, throughout virus infections, a thorough clarification of the virus-host immune system interactions will be most probably helpful to encounter these challenges. Emerging evidence suggests that just like SARS and MERS, COVID-19 primarily suppresses the innate immune system, enabling its stable propagation during the early stage of infection. Consequently, proinflammatory cytokines and chemokines have been increasing during infection progression associated with severe lung pathology. It is imperative to consider hyper inflammation in vaccine designing, as vaccine-induced immune responses must have a protective role against infection without leading to immunopathology. Among the front-line responders to viral infections, Natural Killer (NK) cells have immense therapeutic potential, forming a bridge between innate and adaptive responses. A subset of NK cells exhibits putatively increased effector functions against viruses following pathogen-specific and immunization. Memory NK cells have higher cytotoxicity and effector activity, compared with the conventional NK cells. As a pioneering strategy, prompt accumulation and long-term maintenance of these memory NK cells could be an efficacious viral treatment. According to the high prevalence of human cytomegalovirus (HCMV) infection in the world, it remains to be determined whether HCMV adaptive NK cells could play a protective role against this new emerging virus. In addition, the new adaptive-like KIR+NKG2C+ NK cell subset (the adaptive-like lung tissue residue [tr]NK cell) in the context of the respiratory infection at this site could specifically exhibit the expansion upon COVID-19. Another aspect of NK cells we should note, utilizing modified NK cells such as allogeneic off-the-shelf CAR-NK cells as a state-of-the-art strategy for the treatment of COVID-19. In this line, we speculate introducing NKG2C into chimeric antigen receptors in NK cells might be a potential approach in future viral immunotherapy for emerging viruses. In this contribution, we will briefly discuss the current status and future perspective of NK cells, which provide to successfully exploit NK cell-mediated antiviral activity that may offer important new tools in COVID-19 treatment.
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Project description:During hematopoiesis, hematopoietic stem cells constantly differentiate into granulocytes and macrophages via a distinct differentiation program that is tightly controlled by myeloid lineage-specific transcription factors. Mice with a null mutation of IFN regulatory factor 8 (IRF8) accumulate CD11b(+)Gr1(+) myeloid cells that phenotypically and functionally resemble tumor-induced myeloid-derived suppressor cells (MDSCs), indicating an essential role of IRF8 in myeloid cell lineage differentiation. However, IRF8 is expressed in various types of immune cells, and whether IRF8 functions intrinsically or extrinsically in regulation of myeloid cell lineage differentiation is not fully understood. In this study, we report an intriguing finding that, although IRF8-deficient mice exhibit deregulated myeloid cell differentiation and resultant accumulation of CD11b(+)Gr1(+) MDSCs, surprisingly, mice with IRF8 deficiency only in myeloid cells exhibit no abnormal myeloid cell lineage differentiation. Instead, mice with IRF8 deficiency only in T cells exhibited deregulated myeloid cell differentiation and MDSC accumulation. We further demonstrated that IRF8-deficient T cells exhibit elevated GM-CSF expression and secretion. Treatment of mice with GM-CSF increased MDSC accumulation, and adoptive transfer of IRF8-deficient T cells, but not GM-CSF-deficient T cells, increased MDSC accumulation in the recipient chimeric mice. Moreover, overexpression of IRF8 decreased GM-CSF expression in T cells. Our data determine that, in addition to its intrinsic function as an apoptosis regulator in myeloid cells, IRF8 also acts extrinsically to repress GM-CSF expression in T cells to control myeloid cell lineage differentiation, revealing a novel mechanism that the adaptive immune component of the immune system regulates the innate immune cell myelopoiesis in vivo.
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Project description:Prior work using allogeneic bone marrow transplantation (allo-BMT) models showed that peritransplant administration of flagellin, a toll-like receptor 5 (TLR5) agonist protected murine allo-BMT recipients from CMV infection while limiting graft-vs-host disease (GvHD). However, the mechanism by which flagellin-TLR5 interaction promotes anti-CMV immunity was not defined. Here, we investigated the anti-CMV immunity of NK cells in C57BL/6 (B6) mice treated with a highly purified cGMP grade recombinant flagellin variant CBLB502 (rflagellin) followed by murine CMV (mCMV) infection. A single dose of rflagellin administered to mice between 48 to 72 hours prior to MCMV infection resulted in optimal protection from mCMV lethality. Anti-mCMV immunity in rflagellin-treated mice correlated with a significantly reduced liver viral load and increased numbers of Ly49H+ and Ly49D+ activated cytotoxic NK cells. Additionally, the increased anti-mCMV immunity of NK cells was directly correlated with increased numbers of IFN-γ, granzyme B- and CD107a producing NK cells following mCMV infection. rFlagellin-induced anti-mCMV immunity was TLR5-dependent as rflagellin-treated TLR5 KO mice had ∼10-fold increased liver viral load compared with rflagellin-treated WT B6 mice. However, the increased anti-mCMV immunity of NK cells in rflagellin-treated mice is regulated indirectly as mouse NK cells do not express TLR5. Collectively, these data suggest that rflagellin treatment indirectly leads to activation of NK cells, which may be an important adjunct benefit of administering rflagellin in allo-BMT recipients.
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Project description:Cytomegalovirus (CMV) is one of the most commonly recognized opportunistic pathogens and remains the most influential known parameter in shaping an individual's immune system. As such, T cells induced by CMV infection could have a long-term impact on subsequent immune responses. Accumulating evidence indicates that memory T cells developed during past bacterial and viral infection can cross-react with unrelated pathogens, including transplant antigens, and can alter responses to de novo infections, vaccines, cancers, or rejection. Therefore, careful examination of T cell responses elicited by CMV is warranted to understand their potentially beneficial or harmful roles in future major immune events. Our detailed exploration of the distribution, phenotype, TCR repertoire and transcriptome of CD4+ T cells within CMV seropositive healthy individuals using high-dimensional flow cytometry and single cell multi-omics sequencing reveals that CMV seropositivity has highly significant age-independent effects, leading to a reduction in CD4+ naïve T cells and an expansion of CD4+ effector memory T cells and CD45RA+ effector memory T cells. These induced CD4+ effector memory T cells undergo a specific differentiation trajectory resulting in a subpopulation of CD57+CD27-CD28-CD244+ CD4+ T cells with cytotoxic function and TCR oligoclonality for optimal controlled coexistence with cytomegalovirus. Through gene set enrichment analysis, we found that this subpopulation is similar to virus-specific CD8+ T cells and T cells that mediate acute rejection in patients using tacrolimus and belatacept, a selective costimulation blocker. Together, these data suggest that memory CD4+ T cells induced by cytomegalovirus are formed via a distinct differentiation program to acquire cytotoxic function and can be potentially detrimental to transplant patients adopting costimulation blockade immunosuppressive regimen.
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