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Peptidylprolyl isomerase C (Ppic) regulates invariant Natural Killer T cell (iNKT) differentiation in mice.

ABSTRACT: Peptidyl-prolyl cis-trans isomerase C (Ppic) is expressed in several bone marrow (BM) hematopoietic progenitors and in T-cell precursors. Since the expression profile of Ppic in the hematoimmune system was suggestive that it could play a role in hematopoiesis and/or T lymphocyte differentiation, we sought to test that hypothesis in vivo. Specifically, we generated a Ppic-deficient mouse model by targeting the endogenous locus by CRISPR/Cas9 and tested the requirement of Ppic in hematopoiesis. Several immune cell lineages covering BM progenitors, lymphocyte precursors, as well as mature cells at the periphery were analyzed. While most lineages were unaffected, invariant NKT (iNKT) cells were reduced in percentage and absolute cell numbers in the Ppic-deficient thymus. This affected the most mature stages in the thymus, S2 and S3, and the phenotype was maintained at the periphery. Additionally, immature transitional T1 and T2 B lymphocytes were increased in the Ppic-deficient spleen, but the phenotype was lost in mature B lymphocytes. In sum, our data show that Ppic is dispensable for myeloid cells, platelets, erythrocytes, αβ, and γδ T lymphocytes in vivo in the steady state, while being involved in B- and iNKT cell differentiation.

SUBMITTER: Paiva RS

PROVIDER: S-EPMC8453708 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Invariant Natural Killer T (iNKT) cells are a subset of T cells recognizing glycolipid antigens presented by CD1d. Human iNKT cells express a conserved T cell receptor (TCR)-α chain (Vα24-Jα18) paired with a specific beta chain, Vβ11. The cells are both innate-like, with rapid cytokine release, and adaptive-like, including thymic positive selection. Over activation of iNKT cells can mediate tissue injury and inflammation in multiple organ systems and play a role in mediating the pathology associated with clinically important inflammatory diseases. At the same time, iNKT cell activation can play a role in protecting against infectious disease and cancer or modulate certain autoimmune diseases through its impact on both the innate and adaptive immune system. This suggests that approaches to cause iNKT cell reduction and/or depletion could treat inflammatory diseases while approaches to promote activation may have therapeutic potential in certain infections, cancer or autoimmune disease. This report summarizes the characterization of a humanized monoclonal depleting antibody (NKTT120) in the cynomolgus macaque. NKTT120 is being developed to treat iNKT mediated inflammation that is associated with chronic inflammatory conditions like sickle cell disease and asthma. NKTT120 binds to human iTCRs and to FCγRI and FCγRIII and has been shown to kill target cells in an ADCC assay at low concentrations consistent with the FCγR binding. iNKT cells were depleted within 24 hours in cynomolgus macaques, but T cell, B cell, and NK cell frequencies were unchanged. iNKT cell recovery was dose and time dependent. T cell dependent antigen responses were not impaired by NKTT120 mediated iNKT depletion as measured by response to KLH challenge. NKTT120 administration did not induce an inflammatory cytokine release at doses up to 10 mg/kg. These data support the use of NKTT120 as an intervention in inflammatory diseases where iNKT reduction or depletion could be beneficial.

Project description:BackgroundInfluenza A virus (IAV) infection leads to significant morbidity and mortality. Biological sex influences the immune responses to IAV infection, resulting in higher mortality in women of reproductive age. Previous studies revealed increased activation of T and B cells in female mice after IAV infection, but extensive analysis of sex differences in both innate and adaptive immune cells over time is lacking. Invariant natural killer T (iNKT) cells are fast-reacting forces and modulators of immune responses that are important to IAV immunity, but it is not known if the presence and function of iNKT cells differ between females and males. The aim of this study was to determine immunological mechanisms that contribute to the increased disease severity in female mice during IAV infection.MethodsFemale and male mice were infected with mouse-adapted IAV and monitored for weight loss and survival. Immune cell populations and cytokine expression in bronchoalveolar lavage fluid, lung, and mediastinal lymph node were determined at three time points after infection using flow cytometry and ELISA.ResultsThe results reveal increased severity and mortality in adult female mice compared to age-matched males. Female mice show larger increases in innate and adaptive immune cell populations and cytokine production in lung compared to mock on Day 6 postinfection. On Day 9 postinfection, female mice express higher numbers of iNKT cells in lung and liver compared to males.ConclusionsThis comprehensive analysis of immune cells and cytokines over time following IAV infection reveals increased leukocyte expansion and stronger proinflammatory cytokine responses in female mice during disease initiation. Furthermore, this is the first study to report a sex bias in iNKT cell populations after IAV infection. The data suggests that the process of recovery from IAV-induced airway inflammation is associated with increased expansion of several different iNKT cell subpopulations in female mice.

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Peptidylprolyl isomerase C (Ppic) regulates invariant Natural Killer T cell (iNKT) differentiation in mice.

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