Rexhepi, F. | bioRxiv Science

bioRxiv2026

Trans-presentation of IL-15 by IL15Rα attenuates tumor immune surveillance and is dispensable for IL-15-dependent tumor growth control

BackgroundIL-15 is a promising cytokine for cancer immunotherapy. IL-15 promotes differentiation and homeostasis of innate and adaptive immune cells, and their cytolytic effector functions. IL-15 receptor is composed of IL-15R, IL-15R{beta} and the common {gamma}c chains. IL-15 is also trans-presented as IL-15R:IL-15 complex to IL-15R{beta}:{gamma}c on neighboring cells. IL-15R is dispensable for early immune response to infections and in autoimmune diabetes. The role of IL-15R in antitumor immune responses remains unclear. MethodsIn WT, Il15-/- and Il15ra-/- mice, we studied the growth of syngeneic tumor cell lines and tumor immune surveillance against endogenous fibrosarcoma induced by methylcholanthrene (MCA). Immune gene signature and total proteome analysis were performed on MCA-induced tumors. ResultsLack of IL-15 or IL-15R did not enhance the growth of implanted tumor cell lines, despite reduced immune cell infiltration. MCA-induced tumor incidence was reduced in mice lacking IL-15R but not IL-15, although both are required for efficient tumor immunoediting. Il15-/- and Il15ra-/- tumors showed reduced Ifng expression but displayed differential modulation of Ifng-responsive genes. Proteome profiles of Il15-/- tumors, but not tumor-derived cell lines, showed significant reduction of antigen presentation pathways. B16-F10 melanoma cells expressing NLRC5, the IFN{gamma}-induced transcriptional activator of tumor antigen presentation, still required IL-15 but not IL-15R for efficient tumor control. ConclusionsOur findings show that IL-15 plays a negligible role in immunosurveillance against spontaneous tumor development, whereas IL-15R restrains immunosurveillance. Neither IL-15 nor IL-15R have a significant impact on implanted tumor models, although IL-15 facilitates efficient control of highly immunogenic tumors for which IL-15R is dispensable.

immunology↗

bioRxiv2023

SARS-CoV-2 spike antigen-specific B cell and antibody responses in pre-vaccination period COVID-19 convalescent males and females with or without post-covid condition

BackgroundFollowing SARS-CoV-2 infection a significant proportion of convalescent individuals develop the post-COVID condition (PCC) that is characterized by wide spectrum of symptoms encompassing various organs. Even though the underlying pathophysiology of PCC is not known, detection of viral transcripts and antigens in tissues other than lungs raise the possibility that PCC may be a consequence of aberrant immune response to the viral antigens. To test this hypothesis, we evaluated B cell and antibody responses to the SARS-CoV-2 antigens in PCC patients who experienced mild COVID-19 disease during the pre-vaccination period of COVID-19 pandemic. MethodsThe study subjects included unvaccinated male and female subjects who developed PCC or not (No-PCC) after clearing RT-PCR confirmed mild COVID-19 infection. SARS-CoV-2 D614G and omicron RBD specific B cell subsets in peripheral circulation were assessed by flow cytometry. IgG, IgG3 and IgA antibody titers toward RBD, spike and nucleocapsid antigens in the plasma were evaluated by ELISA. ResultsThe frequency of the B cells specific to D614G-RBD were comparable in convalescent groups with and without PCC in both males and females. Notably, in females with PCC, the anti-D614G RBD specific double negative (IgD-CD27-) B cells showed significant correlation with the number of symptoms at acute of infection. Anti-spike antibody responses were also higher at 3 months post-infection in females who developed PCC, but not in the male PCC group. On the other hand, the male PCC group also showed consistently high anti-RBD IgG responses compared to all other groups. ConclusionsThe antibody responses to the spike protein, but not the RBD-specific B cell responses diverge between convalescent males and females, and those who develop PCC or not. Our findings suggest that sex-related factors may also be involved in the development of PCC via modulating antibody responses to the SARS-CoV-2 antigens. Short SummaryPost-COVID Condition (PCC) is lingering illness that afflicts a significant proportion of COVID-19 patients from three months after clearing SARS-CoV-2 infection. Therapy for PCC is only palliative and the underlying disease mechanisms are unclear. The wide spectrum of PCC symptoms that can affect different organs and the detection of viral components in tissues distant from lungs raise the possibility that PCC may be associated with aberrant immune response due to presence of viral antigens. Therefore, we studied B cell and antibody responses to the spike and nucleoprotein antigens in PCC patients who cleared mild SARS-CoV-2 infection during the pre-vaccination COVID-19 pandemic period. We observed divergent patterns of immune reactivity to the spike protein in PCC males and females at different times post-infection, suggesting that the immune responses in PCC may also be influenced by sex-related factors.

immunology↗