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2.
Pathogens ; 10(10)2021 Oct 01.
Article in English | MEDLINE | ID: mdl-34684216

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 231 million people globally, with more than 4.7 million deaths recorded by the World Health Organization as of 26 September 2021. In response to the pandemic, some countries (New Zealand, Vietnam, Taiwan, South Korea and others) have pursued suppression strategies, so-called Zero COVID policies, to drive and maintain infection rates as close to zero as possible and respond aggressively to new cases. In comparison, European countries and North America have adopted mitigation strategies (of varying intensity and effectiveness) that aim primarily to prevent health systems from being overwhelmed. With recent advances in our understanding of SARS-CoV-2 and its biology, and the increasing recognition there is more to COVID-19 beyond the acute infection, we offer a perspective on some of the long-term risks of mutational escape, viral persistence, reinfection, immune dysregulation and neurological and multi-system complications (Long COVID).

3.
Front Immunol ; 11: 600405, 2020.
Article in English | MEDLINE | ID: mdl-33408715

ABSTRACT

Aberrant T cell differentiation and lymphopenia are hallmarks of severe COVID-19 disease. Since T cells must race to cull infected cells, they are quick to differentiate and achieve cytotoxic function. With this responsiveness, comes hastened apoptosis, due to a coupled mechanism of death and differentiation in both CD4+ and CD8+ lymphocytes via CD95 (Fas) and serine-threonine kinase (Akt). T cell lymphopenia in severe cases may represent cell death or peripheral migration. These facets depict SARS-Cov-2 as a lympho-manipulative pathogen; it distorts T cell function, numbers, and death, and creates a dysfunctional immune response. Whether preservation of T cells, prevention of their aberrant differentiation, and expansion of their population may alter disease course is unknown. Its investigation requires experimental interrogation of the linked differentiation and death pathway by agents known to uncouple T cell proliferation and differentiation in both CD4+ and CD8+ T cells.


Subject(s)
Apoptosis/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Cell Differentiation/immunology , Proto-Oncogene Proteins c-akt/immunology , SARS-CoV-2/immunology , fas Receptor/immunology , CD4-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/pathology , COVID-19/pathology , Humans
4.
JCI Insight ; 2(23)2017 12 07.
Article in English | MEDLINE | ID: mdl-29212954

ABSTRACT

Adoptive immunotherapies using T cells genetically redirected with a chimeric antigen receptor (CAR) or T cell receptor (TCR) are entering mainstream clinical practice. Despite encouraging results, some patients do not respond to current therapies. In part, this phenomenon has been associated with infusion of reduced numbers of early memory T cells. Herein, we report that AKT signaling inhibition is compatible with CAR and TCR retroviral transduction of human T cells while promoting a CD62L-expressing central memory phenotype. Critically, this intervention did not compromise cell yield. Mechanistically, disruption of AKT signaling preserved MAPK activation and promoted the intranuclear localization of FOXO1, a transcriptional regulator of T cell memory. Consequently, AKT signaling inhibition synchronized the transcriptional profile for FOXO1-dependent target genes across multiple donors. Expression of an AKT-resistant FOXO1 mutant phenocopied the influence of AKT signaling inhibition, while addition of AKT signaling inhibition to T cells expressing mutant FOXO1 failed to further augment the frequency of CD62L-expressing cells. Finally, treatment of established B cell acute lymphoblastic leukemia was superior using anti-CD19 CAR-modified T cells transduced and expanded in the presence of an AKT inhibitor compared with conventionally grown T cells. Thus, inhibition of signaling along the PI3K/AKT axis represents a generalizable strategy to generate large numbers of receptor-modified T cells with an early memory phenotype and superior antitumor efficacy.


Subject(s)
Immunotherapy, Adoptive/methods , Proto-Oncogene Proteins c-akt/immunology , Receptors, Chimeric Antigen/immunology , T-Lymphocyte Subsets/immunology , Tissue Engineering/methods , Animals , Cell Differentiation , Female , Forkhead Box Protein O1/metabolism , Gene Expression Regulation/immunology , Humans , Immunologic Memory , L-Selectin/metabolism , Lymphocyte Activation/immunology , Mice, Inbred NOD , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Signal Transduction/immunology , Transduction, Genetic/methods , Xenograft Model Antitumor Assays
5.
J Clin Invest ; 126(1): 318-34, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26657860

ABSTRACT

Adoptive cell transfer (ACT) of purified naive, stem cell memory, and central memory T cell subsets results in superior persistence and antitumor immunity compared with ACT of populations containing more-differentiated effector memory and effector T cells. Despite a clear advantage of the less-differentiated populations, the majority of ACT trials utilize unfractionated T cell subsets. Here, we have challenged the notion that the mere presence of less-differentiated T cells in starting populations used to generate therapeutic T cells is sufficient to convey their desirable attributes. Using both mouse and human cells, we identified a T cell-T cell interaction whereby antigen-experienced subsets directly promote the phenotypic, functional, and metabolic differentiation of naive T cells. This process led to the loss of less-differentiated T cell subsets and resulted in impaired cellular persistence and tumor regression in mouse models following ACT. The T memory-induced conversion of naive T cells was mediated by a nonapoptotic Fas signal, resulting in Akt-driven cellular differentiation. Thus, induction of Fas signaling enhanced T cell differentiation and impaired antitumor immunity, while Fas signaling blockade preserved the antitumor efficacy of naive cells within mixed populations. These findings reveal that T cell subsets can synchronize their differentiation state in a process similar to quorum sensing in unicellular organisms and suggest that disruption of this quorum-like behavior among T cells has potential to enhance T cell-based immunotherapies.


Subject(s)
Immunologic Memory , Immunotherapy, Adoptive , T-Lymphocytes/immunology , Animals , Cell Differentiation , Fas Ligand Protein/physiology , Female , Melanoma, Experimental/therapy , Mice , Mice, Inbred C57BL , Proto-Oncogene Proteins c-akt/physiology , T-Lymphocytes/cytology , fas Receptor/physiology
6.
J Exp Med ; 210(10): 1961-76, 2013 Sep 23.
Article in English | MEDLINE | ID: mdl-23999499

ABSTRACT

Dendritic cells (DCs) comprise distinct populations with specialized immune-regulatory functions. However, the environmental factors that determine the differentiation of these subsets remain poorly defined. Here, we report that retinoic acid (RA), a vitamin A derivative, controls the homeostasis of pre-DC (precursor of DC)-derived splenic CD11b(+)CD8α(-)Esam(high) DCs and the developmentally related CD11b(+)CD103(+) subset within the gut. Whereas mice deprived of RA signaling significantly lost both of these populations, neither pre-DC-derived CD11b(-)CD8α(+) and CD11b(-)CD103(+) nor monocyte-derived CD11b(+)CD8α(-)Esam(low) or CD11b(+)CD103(-) DC populations were deficient. In fate-tracking experiments, transfer of pre-DCs into RA-supplemented hosts resulted in near complete conversion of these cells into the CD11b(+)CD8α(-) subset, whereas transfer into vitamin A-deficient (VAD) hosts caused diversion to the CD11b(-)CD8α(+) lineage. As vitamin A is an essential nutrient, we evaluated retinoid levels in mice and humans after radiation-induced mucosal injury and found this conditioning led to an acute VAD state. Consequently, radiation led to a selective loss of both RA-dependent DC subsets and impaired class II-restricted auto and antitumor immunity that could be rescued by supplemental RA. These findings establish a critical role for RA in regulating the homeostasis of pre-DC-derived DC subsets and have implications for the management of patients with immune deficiencies resulting from malnutrition and irradiation.


Subject(s)
Dendritic Cells/immunology , Dendritic Cells/metabolism , Homeostasis/immunology , Tretinoin/metabolism , Animals , Cell Differentiation/immunology , Cell Proliferation , Cell Survival , Dendritic Cells/cytology , Dendritic Cells/radiation effects , Female , Histocompatibility Antigens Class II/immunology , Humans , Immunophenotyping , Intestinal Mucosa/metabolism , Intestines/immunology , Intestines/radiation effects , Mice , Neoplasms/immunology , Neoplasms/metabolism , Organ Specificity/immunology , Phenotype , Receptors, Retinoic Acid/metabolism , Signal Transduction , Spleen/immunology , Spleen/metabolism , Spleen/radiation effects , Vitamin A/metabolism , Whole-Body Irradiation/adverse effects
7.
Mol Ther ; 21(7): 1369-77, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23568260

ABSTRACT

Engineering CD8⁺ T cells to deliver interleukin 12 (IL-12) to the tumor site can lead to striking improvements in the ability of adoptively transferred T cells to induce the regression of established murine cancers. We have recently shown that IL-12 triggers an acute inflammatory environment that reverses dysfunctional antigen presentation by myeloid-derived cells within tumors and leads to an increase in the infiltration of adoptively transferred antigen-specific CD8⁺ T cells. Here, we find that local delivery of IL-12 increased the expression of Fas within tumor-infiltrating macrophages, dendritic cells, and myeloid-derived suppressor cells (MDSC), and that these changes were abrogated in mice deficient in IL-12-receptor signaling. Importantly, upregulation of Fas in host mice played a critical role in the proliferation and antitumor activity of adoptively transferred IL-12-modified CD8⁺ T cells. We also observed higher percentages of myeloid-derived cell populations within tumors in Fas-deficient mice, indicating that tumor stromal destruction was dependent on the Fas death receptor. Taken together, these results describe the likely requirement for costimulatory reverse signaling through Fasl on T cells that successfully infiltrate tumors, a mechanism triggered by the induction of Fas expression on myeloid-derived cells by IL-12 and the subsequent collapse of the tumor stroma.


Subject(s)
Interleukin-12/therapeutic use , Melanoma, Experimental/metabolism , fas Receptor/metabolism , Animals , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Dendritic Cells/metabolism , Female , Flow Cytometry , Interleukin-12/administration & dosage , Melanoma, Experimental/therapy , Mice , Mice, Inbred C57BL , Mice, Transgenic , fas Receptor/genetics
8.
J Clin Invest ; 121(12): 4746-57, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22056381

ABSTRACT

Solid tumors are complex masses with a local microenvironment, or stroma, that supports tumor growth and progression. Among the diverse tumor-supporting stromal cells is a heterogeneous population of myeloid-derived cells. These cells are alternatively activated and contribute to the immunosuppressive environment of the tumor; overcoming their immunosuppressive effects may improve the efficacy of cancer immunotherapies. We recently found that engineering tumor-specific CD8(+) T cells to secrete the inflammatory cytokine IL-12 improved their therapeutic efficacy in the B16 mouse model of established melanoma. Here, we report the mechanism underlying this finding. Surprisingly, direct binding of IL-12 to receptors on lymphocytes or NK cells was not required. Instead, IL-12 sensitized bone marrow-derived tumor stromal cells, including CD11b(+)F4/80(hi) macrophages, CD11b(+)MHCII(hi)CD11c(hi) dendritic cells, and CD11b(+)Gr-1(hi) myeloid-derived suppressor cells, causing them to enhance the effects of adoptively transferred CD8(+) T cells. This reprogramming of myeloid-derived cells occurred partly through IFN-γ. Surprisingly, direct presentation of antigen to the transferred CD8(+) T cells by tumor was not necessary; however, MHCI expression on host cells was essential for IL-12-mediated antitumor enhancements. These results are consistent with a model in which IL-12 enhances the ability of CD8(+) T cells to collapse large vascularized tumors by triggering programmatic changes in otherwise suppressive antigen-presenting cells within tumors and support the use of IL-12 as part of immunotherapy for the treatment of solid tumors.


Subject(s)
CD8-Positive T-Lymphocytes/transplantation , Gene Expression Regulation, Neoplastic/drug effects , Immunotherapy, Adoptive , Interleukin-12/physiology , Melanoma, Experimental/therapy , Myeloid Cells/physiology , Tumor Escape/immunology , Tumor Microenvironment/immunology , Animals , Antigen Presentation , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/pathology , Antigens, Neoplasm/immunology , Bone Marrow Cells/immunology , Bone Marrow Cells/pathology , CD8-Positive T-Lymphocytes/metabolism , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/immunology , Inflammation/genetics , Interferon-gamma/physiology , Interleukin-12/genetics , Interleukin-12/metabolism , Lymphocyte Subsets/immunology , Lymphocyte Subsets/pathology , Macrophages/physiology , Melanoma, Experimental/immunology , Melanoma, Experimental/pathology , Mice , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Neoplasm Proteins/immunology , Radiation Chimera , Recombinant Fusion Proteins/physiology , Stromal Cells/pathology , Stromal Cells/physiology
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